When Mehmed II ascended the throne again in 1451 he devoted himself to strengthening the Ottoman navy and made preparations for an attack on Constantinople. In the narrow Bosphorus Straits, the fortress Anadoluhisarı had been built by his great-grandfather Bayezid I on the Asian side; Mehmed erected an even stronger fortress called Rumelihisarı on the European side, and thus gained complete control of the strait. Having completed his fortresses, Mehmed proceeded to levy a toll on ships passing within reach of their cannon. A Venetian vessel ignoring signals to stop was sunk with a single shot and all the surviving sailors beheaded, except for the captain, who was impaled and mounted as a human scarecrow as a warning to further sailors on the strait.

Abu Ayyub al-Ansari, the companion and standard bearer of Muhammad, had died during the first Siege of Constantinople (674-678). As Mehmed II's army approached Constantinople, Mehmed's sheikh Akshamsaddin discovered the tomb of Abu Ayyub al-Ansari. After the conquest, Mehmed built Eyüp Sultan Mosque at the site to emphasize the importance of the conquest to the Islamic world and highlight his role as ghazi.

In 1453 Mehmed commenced the siege of Constantinople with

• an army between 80,000 and 200,000 troops,
• an artillery train of over seventy large field pieces, and
• a navy of 320 vessels, the bulk of them transports and storeships.

The city was surrounded by sea and land; the fleet at the entrance of the Bosphorus stretched from shore to shore in the form of a crescent, to intercept or repel any assistance for Constantinople from the sea. In early April, the Siege of Constantinople began. At first, the city's walls held off the Turks, even though Mehmed's army used the new bombard designed by Orban, a giant cannon similar to the Dardanelles Gun. The harbour of the Golden Horn was blocked by a boom chain and defended by twenty-eight warships.

On 22 April, Mehmed transported his lighter warships overland, around the Genoese colony of Galata, and into the Golden Horn's northern shore; eighty galleys were transported from the Bosphorus after paving a route, little over one mile, with wood. Thus the Byzantines stretched their troops over a longer portion of the walls. About a month later, Constantinople fell, on 29 May, following a fifty-seven-day siege. After this conquest, Mehmed moved the Ottoman capital from Adrianople to Constantinople.

Mehmed II's first campaigns after Constantinople were in the direction of Serbia, which had been an Ottoman vassal state since the Battle of Kosovo in 1389. The Ottoman ruler had a connection with the Serbian Despotate – one of Murad II’s wives was Mara Branković – and he used that fact to claim some Serbian islands. That Đurađ Branković had recently made an alliance with the Hungarians, and had paid the tribute irregularly, may have been important considerations. When Serbia refused these demands, the Ottoman army set out from Edirne towards Serbia in 1454. Smederevo was besieged, as was Novo Brdo, the most important Serbian metal mining and smelting centre. Ottomans and Hungarians fought during the years till 1456.

The Ottoman army advanced as far as Belgrade, where it attempted but failed to conquer the city from John Hunyadi at the Siege of Belgrade, on 14 July 1456. A period of relative peace ensued in the region until the Fall of Belgrade in 1521, during the reign of Mehmed’s great-grandson, known as Sultan Suleiman the Magnificent. The sultan retreated to Edirne, and Đurađ Branković regained possession of some parts of Serbia. Before the end of the year, however, the 79-year-old Branković died. Serbian independence survived him for only two years, when the Ottoman Empire formally annexed his lands following dissension among his widow and three remaining sons. Lazar, the youngest, poisoned his mother and exiled his brothers, but he died soon afterwards. In the continuing turmoil the oldest brother Stefan Branković gained the throne but was ousted in March 1459. After that the Serbian throne was offered to Stephen Tomašević, the future king of Bosnia, which infuriated Sultan Mehmed. He sent his army, which captured Smederevo in June 1459, ending the existence of the Serbian Despotate.

The Despotate of the Morea bordered the southern Ottoman Balkans. The Ottomans had already invaded the region under Murad II, destroying the Byzantine defences — the Hexamilion wall — at the Isthmus of Corinth in 1446. Before the final siege of Constantinople Mehmed ordered Ottoman troops to attack the Morea. The despots, Demetrios Palaiologos and Thomas Palaiologos, brothers of the last emperor, failed to send any aid. Their own incompetence resulted in an Albanian-Greek revolt against them, during which they invited in Ottoman troops to help put down the revolt. At this time, a number of influential Moreote Greeks and Albanians made private peace with Mehmed. After more years of incompetent rule by the despots, their failure to pay their annual tribute to the Sultan, and finally their own revolt against Ottoman rule, Mehmed entered the Morea in May 1460. Demetrios ended up a prisoner of the Ottomans and his younger brother Thomas fled. By the end of the summer, the Ottomans had achieved the submission of virtually all cities possessed by the Greeks.

A few holdouts remained for a time. The island of Monemvasia refused to surrender, and it was ruled for a brief time by a Catalan corsair. When the population drove him out they obtained the consent of Thomas to submit to the Pope's protection before the end of 1460. The Mani Peninsula, on the Morea's south end, resisted under a loose coalition of local clans, and the area then came under the rule of Venice. The very last holdout was Salmeniko, in the Morea's northwest. Graitzas Palaiologos was the military commander there, stationed at Salmeniko Castle (also known as Castle Orgia). While the town eventually surrendered, Graitzas and his garrison and some town residents held out in the castle until July 1461, when they escaped and reached Venetian territory.

Emperors of Trebizond formed alliances through royal marriages with various Muslim rulers. Emperor John IV of Trebizond married his daughter to the son of his brother-in-law, Uzun Hasan, khan of the Ak Koyunlu, in return for his promise to defend Trebizond. He also secured promises of support from the Turkish beys of Sinope and Karamania, and from the king and princes of Georgia. The Ottomans were motivated to capture Trebizond or to get an annual tribute. In the time of Murad II they first attempted to take the capital by sea in 1442, but high surf made the landings difficult and the attempt was repulsed. While Mehmed II was away laying siege to Belgrade in 1456, the Ottoman governor of Amasya attacked Trebizond, and although he was defeated, he took many prisoners and extracted a heavy tribute.

After John's death in 1459, his brother David came to power and intrigued with various European powers for help against the Ottomans, speaking of wild schemes that included the conquest of Jerusalem. Mehmed II eventually heard of these intrigues and was further provoked to action by David's demand that Mehmed remit the tribute imposed on his brother.

Mehmed the Conqueror¹’s response came in the summer of 1461. He led a sizable army from Bursa by land and the Ottoman navy by sea, first to Sinope, joining forces with Ismail's brother Ahmed (the Red). He captured Sinope and ended the official reign of the Jandarid dynasty, although he appointed Ahmed as the governor of Kastamonu and Sinope, only to revoke the appointment the same year. Various other members of the Jandarid dynasty were offered important functions throughout the history of the Ottoman Empire. During the march to Trebizond, Uzun Hasan sent his mother Sara Khatun as an ambassador; while they were climbing the steep heights of Zigana on foot, she asked Sultan Mehmed why he was undergoing such hardship for the sake of Trebizond. Mehmed replied:

“Mother, in my hand is the sword of Islam, without this hardship I should not deserve the name of ghazi, and today and tomorrow I should have to cover my face in shame before Allah.”

Having isolated Trebizond, Mehmed quickly swept down upon it before the inhabitants knew he was coming, and he placed it under siege. The city held out for a month before the emperor David surrendered on 15 August 1461.

Wallachia as pictured in the 1493 Nuremberg Chronicle.

The Ottomans since the early 15th century tried to bring Wallachia (Ottoman Turkish: والاچیا‎) under their control by putting their own candidate on the throne, but each attempt ended in failure. The Ottomans regarded Wallachia as a buffer zone between them and the Kingdom of Hungary and for a yearly tribute did not meddle in their internal affairs. The two primary Balkan powers, Hungary and the Ottomans, maintained an enduring struggle to make Wallachia their own vassal. To prevent Wallachia from falling into the Hungarian fold, the Ottomans freed young Vlad III (Dracula), who had spent four years as a prisoner of Murad, together with his brother Radu, so that Vlad could claim the throne of Wallachia. His rule was short-lived, however, as Hunyadi invaded Wallachia and restored his ally Vladislav II, of the Dănești clan, to the throne.

Vlad III Dracula fled to Moldavia, where he lived under the protection of his uncle, Bogdan II. In October 1451, Bogdan was assassinated and Vlad fled to Hungary. Impressed by Vlad's vast knowledge of the mindset and inner workings of the Ottoman Empire, as well as his hatred towards the Turks and new Sultan Mehmed II, Hunyadi reconciled with his former enemy and tried to make Vlad III his own adviser, but Vlad refused.

In 1456, three years after the Ottomans had conquered Constantinople, they threatened Hungary by besieging Belgrade. Hunyadi began a concerted counter-attack in Serbia: while he himself moved into Serbia and relieved the siege (before dying of the plague), Vlad III Dracula led his own contingent into Wallachia, reconquered his native land, and killed the impostor Vladislav II.

In 1459, Mehmed II sent envoys to Vlad to urge him to pay a delayed tribute of 10,000 ducats and 500 recruits into the Ottoman forces. Vlad III Dracula refused and had the Ottoman envoys killed by nailing their turbans to their heads, on the pretext that they had refused to raise their "hats" to him, as they only removed their headgear before Allah.

Meanwhile, the Sultan sent the Bey of Nicopolis, Hamza Pasha, to make peace and, if necessary, eliminate Vlad III. Vlad III set an ambush; the Ottomans were surrounded and almost all of them caught and impaled, with Hamza Pasha impaled on the highest stake, as befit his rank.

Territories held by Wallachian prince Mircea the Elder, c. 1390.

In the winter of 1462, Vlad III crossed the Danube and scorched the entire Bulgarian land in the area between Serbia and the Black Sea. Allegedly disguising himself as a Turkish Sipahi and utilizing his command of the Turkish language and customs, Vlad III infiltrated Ottoman camps, ambushed, massacred or captured several Ottoman forces. In a letter to Corvinus dated 2 February, he wrote:

“I have killed peasants men and women, old and young, who lived at Oblucitza and Novoselo, where the Danube flows into the sea, up to Rahova, which is located near Chilia, from the lower Danube up to such places as Samovit and Ghighen. We killed 23,884 Turks without counting those whom we burned in homes or the Turks whose heads were cut by our soldiers. ... Thus, your highness, you must know that I have broken the peace with him [Mehmed II].”

Mehmed II abandoned his siege of Corinth to launch a punitive attack against Vlad III in Wallachia but suffered many casualties in a surprise night attack led by Vlad III Dracula, who was apparently bent on personally killing the Sultan. It is said that when the forces of Mehmed the Conqueror and Radu the Handsome came to Târgoviste, they saw so many Turks impaled around the city that, appalled by the sight, Mehmed considered withdrawing but was convinced by his commanders to stay. However, Vlad's policy of staunch resistance against the Ottomans was not a popular one, and he was betrayed by the boyars's (local aristocracy) appeasing faction, most of them also pro-Dăneşti (a rival princely branch). His best friend and ally Stephen III of Moldavia, who had promised to help him, seized the chance and instead attacked him trying to take back the fortress of Chilia. Vlad III had to retreat to the mountains. After this, the Ottomans captured the Wallachian capital Târgoviște and Mehmed II withdrew, having left Radu as ruler of Wallachia. Turahanoğlu Ömer Bey, who served with distinction and wiped out a force 6,000 Wallachians and deposited 2,000 of their heads at the feet of Mehmed II, was also reinstated, as a reward, in his old gubernatorial post in Thessaly. Vlad eventually escaped to Hungary, where he was imprisoned on a false accusation of treason against his overlord, Matthias Corvinus.

The despot of Serbia, Lazar Branković, died in 1458, and a civil war broke out among his heirs that resulted in the Ottoman conquest of Serbia in 1459. Stephen Tomašević, son of the king of Bosnia, tried to bring Serbia under his control, but Ottoman expeditions forced him to give up his plan and Stephen fled to Bosnia, seeking refuge at the court of his father. After some battles Bosnia became tributary kingdom to the Ottomans.

On 10 July 1461, Stephen Thomas died, and Stephen Tomašević succeeded him as King of Bosnia. In 1461, Stephen Tomašević made an alliance with the Hungarians and asked Pope Pius II for help in the face of an impending Ottoman invasion. In 1463, after a dispute over the tribute paid annually by the Bosnian Kingdom to the Ottomans, he sent for help from the Venetians. However, none ever reached Bosnia. In 1463, Sultan Mehmed II led an army into the country. The royal city of Bobovac soon fell, leaving Stephen Tomašević to retreat to Jajce and later to Ključ. Mehmed invaded Bosnia and conquered it very quickly, executing Stephen Tomašević and his uncle Radivoj. Bosnia officially fell in 1463 and became the westernmost province of the Ottoman Empire.

According to the Byzantine historian Michael Critobulus, hostilities broke out after an Albanian slave of the Ottoman commander of Athens fled to the Venetian fortress of Coron (Koroni) with 100,000 silver aspers from his master's treasure. The fugitive then converted to Christianity, so Ottoman demands for his rendition were refused by the Venetian authorities. Using this as a pretext in November 1462, the Ottoman commander in central Greece, Turahanoğlu Ömer Bey, attacked and nearly succeeded in taking the strategically important Venetian fortress of Lepanto (Nafpaktos). On 3 April 1463, however, the governor of the Morea, Isa Beg, took the Venetian-held town of Argos by treason.

The new alliance launched a two-pronged offensive against the Ottomans: a Venetian army, under the Captain General of the Sea Alvise Loredan, landed in the Morea, while Matthias Corvinus invaded Bosnia. At the same time, Pius II began assembling an army at Ancona, hoping to lead it in person. Negotiations were also begun with other rivals of the Ottomans, such as Karamanids, Uzun Hassan and the Crimean Khanate.

In early August, the Venetians retook Argos and refortified the Isthmus of Corinth, restoring the Hexamilion wall and equipping it with many cannons. They then proceeded to besiege the fortress of the Acrocorinth, which controlled the northwestern Peloponnese. The Venetians engaged in repeated clashes with the defenders and with Ömer Bey's forces, until they suffered a major defeat on 20 October and were then forced to lift the siege and retreat to the Hexamilion and to Nauplia (Nafplion). In Bosnia, Matthias Corvinus seized over sixty fortified places and succeeded in taking its capital, Jajce, after a 3-month siege, on 16 December.

Ottoman reaction was swift and decisive: Mehmed II dispatched his Grand Vizier, Mahmud Pasha Angelović, with an army against the Venetians. To confront the Venetian fleet, which had taken station outside the entrance of the Dardanelles Straits, the Sultan further ordered the creation of the new shipyard of Kadirga Limani in the Golden Horn (named after the "kadirga" type of galley), and of two forts to guard the Straits, Kilidulbahr and Sultaniye. The Morean campaign was swiftly victorious for the Ottomans; they razed the Hexamilion, and advanced into the Morea. Argos fell, and several forts and localities that had recognized Venetian authority reverted to their Ottoman allegiance.

Sultan Mehmed II, who was following Mahmud Pasha with another army to reinforce him, had reached Zeitounion (Lamia) before being apprised of his Vizier's success. Immediately, he turned his men north, towards Bosnia. However, the Sultan's attempt to retake Jajce in July and August 1464 failed, with the Ottomans retreating hastily in the face of Corvinus' approaching army. A new Ottoman army under Mahmud Pasha then forced Corvinus to withdraw, but Jajce was not retaken for many years after. However, the death of Pope Pius II on 15 August in Ancona spelled the end of the Crusade.

In the meantime, the Venetian Republic had appointed Sigismondo Malatesta for the upcoming campaign of 1464. He launched attacks against Ottoman forts and engaged in a failed siege of Mistra in August through October. Small-scale warfare continued on both sides, with raids and counter-raids, but a shortage of manpower and money meant that the Venetians remained largely confined to their fortified bases, while Ömer Bey's army roamed the countryside.

In the Aegean, the Venetians tried to take Lesbos in the spring of 1464, and besieged the capital Mytilene for six weeks, until the arrival of an Ottoman fleet under Mahmud Pasha on 18 May forced them to withdraw. Another attempt to capture the island shortly after also failed. The Venetian navy spent the remainder of the year in ultimately fruitless demonstrations of force before the Dardanelles. In early 1465, Mehmed II sent peace feelers to the Venetian Senate; distrusting the Sultan's motives, these were rejected.

In April 1466, the Venetian war effort was reinvigorated under Vettore Cappello: the fleet took the northern Aegean islands of Imbros, Thasos, and Samothrace, and then sailed into the Saronic Gulf. On 12 July, Cappello landed at Piraeus and marched against Athens, the Ottomans' major regional base. He failed to take the Acropolis and was forced to retreat to Patras, the capital of Peloponnese and the seat of the Ottoman bey, which was being besieged by a joint force of Venetians and Greeks. Before Cappello could arrive, and as the city seemed on the verge of falling, Ömer Bey suddenly appeared with 12,000 cavalry and drove the outnumbered besiegers off. Six hundred Venetians and a hundred Greeks were taken prisoner out of a force of 2,000, while Barbarigo himself was killed. Cappello, who arrived some days later, attacked the Ottomans but was heavily defeated. Demoralized, he returned to Negroponte with the remains of his army. There Cappello fell ill and died on 13 March 1467. In 1470 Mehmed personally led an Ottoman army to besiege Negroponte. The Venetian relief navy was defeated and Negroponte was captured.

In spring 1466, Sultan Mehmed marched with a large army against the Albanians. Under their leader, Skenderbeg, they had long resisted the Ottomans, and had repeatedly sought assistance from Italy. Mehmed II responded by marching again against Albania but was unsuccessful. The winter brought an outbreak of plague, which would recur annually and sap the strength of the local resistance. Skanderbeg himself died of malaria in the Venetian stronghold of Lissus (Lezhë), ending the ability of Venice to use the Albanian lords for its own advantage. After Skanderbeg died, some Venetian-controlled northern Albanian garrisons continued to hold territories coveted by the Ottomans, such as Žabljak Crnojevića, Drisht, Lezha, and Shkodra — the most significant. Mehmed II sent his armies to take Shkodra in 1474 but failed. Then he went personally to lead the siege of Shkodra of 1478-79. The Venetians and Shkodrans resisted the assaults and continued to hold the fortress until Venice ceded Shkodra to the Ottoman Empire in the Treaty of Constantinople as a condition of ending the war.

The agreement was established as a result of the Ottomans having reached the outskirts of Venice. Based on the terms of the treaty, the Venetians were allowed to keep Ulcinj, Antivan, and Durrës. However, they ceded Shkodra, which had been under Ottoman siege for many months, as well as other territories on the Dalmatian coastline, and they relinquished control of the Greek islands of Negroponte (Euboea) and Lemnos. Moreover, the Venetians were forced to pay 100,000 ducat indemnity and agreed to a tribute of around 10,000 ducats per year in order to acquire trading privileges in the Black Sea. As a result of this treaty, Venice acquired a weakened position in the Levant.

During the post-Seljuks era in the second half of the middle ages, numerous Turkmen principalities collectively known as Anatolian beyliks emerged in Anatolia. Karamanids initially centred around the modern provinces of Karaman and Konya, the most important power in Anatolia. But towards the end of the 14th century, Ottomans began to dominate on most of Anatolia, reducing the Karaman influence and prestige.

İbrahim II of Karaman was the ruler of Karaman, and during his last years, his sons began struggling for the throne. His heir apparent was İshak of Karaman, the governor of Silifke. But Pir Ahmet, a younger son, declared himself as the bey of Karaman in Konya. İbrahim escaped to a small city in western territories where he died in 1464. The competing claims to the throne resulted in an interregnum in the beylik. Nevertheless, with the help of Uzun Hasan, the sultan of the Akkoyunlu (White Sheep) Turkmens, İshak was able to ascend to the throne. His reign was short, however, as Pir Ahmet appealed to Sultan Mehmet II for help, offering Mehmet some territory that İshak refused to cede. With Ottoman help, Pir Ahmet defeated İshak in the battle of Dağpazarı. İshak had to be content with Silifke up to an unknown date. Pir Ahmet kept his promise and ceded a part of the beylik to the Ottomans, but he was uneasy about the loss. So during the Ottoman campaign in the West, he recaptured his former territory. Mehmet returned, however, and captured both Karaman (Larende) and Konya in 1466. Pir Ahmet barely escaped to the East. A few years later, Ottoman vizier (later grand vizier) Gedik Ahmet Pasha captured the coastal region of the beylik.

Pir Ahmet as well as his brother Kasım escaped to Uzun Hasan's territory. This gave Uzun Hasan a chance to interfere. In 1472, the Akkoyunlu army invaded and raided most of Anatolia (this was the reason behind the Battle of Otlukbeli in 1473). But then Mehmed led a successful campaign against Uzun Hasan in 1473 that resulted in the decisive victory of the Ottoman Empire in the Battle of Otlukbeli. Before that, Pir Ahmet with Akkoyunlu help had captured Karaman. However Pir Ahmet couldn't enjoy another term. Because immediately after the capture of Karaman, the Akkoyunlu army was defeated by the Ottomans near Beyşehir and Pir Ahmet had to escape once more. Although he tried to continue his struggle, he learned that his family members had been transferred to İstanbul by Gedik Ahmet Pasha, so he finally gave up. Demoralized, he escaped to Akkoyunlu territory where he was given a tımar (fief) in Bayburt. He died in 1474.

Uniting the Anatolian beyliks was first accomplished by Sultan Bayezid I, more than fifty years before Mehmed II but after the destructive Battle of Ankara in 1402, the newly formed unification was gone. Mehmed II recovered Ottoman power over the other Turkish states, and these conquests allowed him to push further into Europe.

Another important political entity that shaped the Eastern policy of Mehmed II were the White Sheep Turcomans. Under the leadership of Uzun Hasan, this kingdom gained power in the East; but because of their strong relations with the Christian powers like the Empire of Trebizond and the Republic of Venice, and the alliance between the Turcomans and the Karamanid tribe, Mehmed saw them as a threat to his own power.

In 1456, Peter III Aaron agreed to pay the Ottomans an annual tribute of 2,000 gold ducats to ensure his southern borders, thus becoming the first Moldavian ruler to accept the Turkish demands. His successor Stephen the Great rejected Ottoman suzerainty and a series of fierce wars ensued. Stephen tried to bring Wallachia under his sphere of influence and so supported his own choice for the Wallachian throne. This resulted in an enduring struggle between different Wallachian rulers backed by Hungarians, Ottomans, and Stephen. An Ottoman army under Hadim Pasha (governor of Rumelia) was sent in 1475 to punish Stephen for his meddling in Wallachia; however, the Ottomans suffered a great defeat at the Battle of Vaslui. Stephen inflicted a decisive defeat on the Ottomans, described as "the greatest ever secured by the Cross against Islam," with casualties, according to Venetian and Polish records, reaching beyond 40,000 on the Ottoman side. Mara Brankovic (Mara Hatun), the former younger wife of Murad II, told a Venetian envoy that the invasion had been worst ever defeat for the Ottomans. Stephen was later awarded the title "Athleta Christi" (Champion of Christ) by Pope Sixtus IV, who referred to him as "verus christianae fidei athleta" ("the true defender of the Christian faith"). Mehmed II assembled a large army and entered Moldavia in June 1476. Meanwhile, groups of Tartars from the Crimean Khanate (the Ottomans' recent ally) were sent to attack Moldavia. Romanian sources may state that they were repelled. Other sources state that joint Ottoman and Crimean Tartar forces "occupied Bessarabia and took Akkerman, gaining control of the southern mouth of the Danube. Stephan tried to avoid open battle with the Ottomans by following a scorched-earth policy".

Finally Stephen faced the Ottomans in battle. The Moldavians luring the main Ottoman forces into a forest that was set on fire, causing some casualties. According to another battle description, the defending Moldavian forces repelled several Ottoman attacks with steady fire from hand-guns. The attacking Turkish Janissaries were forced to crouch on their stomachs instead of charging headlong into the defenders positions. Seeing the imminent defeat of his forces, Mehmed charged with his personal guard against the Moldavians, managing to rally the Janissaries, and turning the tide of the battle. Turkish Janissaries penetrated inside the forest and engaged the defenders in man-to-man fighting.

The Moldavian army was utterly defeated (casualties were very high on both sides), and the chronicles say that the entire battlefield was covered with the bones of the dead, a probable source for the toponym (Valea Albă is Romanian and Akdere Turkish for "The White Valley").

Stephen the Great retreated into the north-western part of Moldavia or even into the Polish Kingdom and began forming another army. The Ottomans were unable to conquer any of the major Moldavian strongholds (Suceava, Neamț, Hotin) and were constantly harassed by small scale Moldavians attacks. Soon they were also confronted with starvation, a situation made worse by an outbreak of the plague, and the Ottoman army returned to Ottoman lands. The threat of Stephen to Wallachia nevertheless ceased.

The Albanian resistance led by George Kastrioti Skanderbeg (İskender Bey), an Albanian noble and a former member of the Ottoman ruling elite, curbed the Ottoman expansion. Skanderbeg had united the Albanian Principalities in a fight against the Empire in the League of Lezhë in 1444. Mehmed II couldn't subjugate Albania while Skanderbeg was alive, even though he twice (1466 and 1467) led the Ottoman armies himself against Krujë. After Skanderbeg died in 1468, the Albanians couldn't find a leader to replace him, and Mehmed II eventually conquered Krujë and Albania in 1478.

Portrait of George Kastrioti Skanderbeg, prince of League of Lezhë

In spring 1466, Sultan Mehmed marched with a large army against the Albanians and their leader, Skenderbeg, who had long resisted the Ottomans, and had repeatedly sought assistance from Italy. For the Albanians, the outbreak of the Ottoman–Venetian War offered a golden opportunity to reassert their independence; for the Venetians, the Albanians provided a useful cover to the Venetian coastal holdings of Durazzo and Scutari. The major result of this campaign was the construction of the fortress of Elbasan, allegedly within just 25 days. This strategically sited fortress, at the lowlands near the end of the old Via Egnatia, cut Albania effectively in half, isolating Skenderbeg's base in the northern highlands from the Venetian holdings in the south. However, following the Sultan's withdrawal Skanderbeg himself spent the winter in Italy, seeking aid. On his return in early 1467, his forces sallied from the highlands, defeated Ballaban Pasha, and lifted the siege of the fortress of Croia (Krujë); they also attacked Elbasan but failed to capture it. Mehmed II responded by marching again against Albania. He energetically pursued the attacks against the Albanian strongholds, while sending detachments to raid the Venetian possessions to keep them isolated. The Ottomans failed again to take Croia, and they failed to subjugate the country. However, the winter brought an outbreak of plague, which would recur annually and sap the strength of the local resistance. Skanderbeg himself died of malaria in the Venetian stronghold of Lissus (Lezhë), ending the ability of Venice to use the Albanian lords for its own advantage. The Albanians were left to their own devices and were gradually subdued over the next decade.

After Skanderbeg died, Mehmed II personally led the siege of Shkodra in 1478-79, of which early Ottoman chronicler Aşıkpaşazade (1400-81) wrote, "All the conquests of Sultan Mehmed were fulfilled with the seizure of Shkodra." The Venetians and Shkodrans resisted the assaults and continued to hold the fortress until Venice ceded Shkodra to the Ottoman Empire in the Treaty of Constantinople as a condition of ending the war.

A number of Turkic peoples, collectively known as the Crimean Tatars, had been inhabiting the peninsula since the early Middle Ages. After the destruction of the Golden Horde by Timur earlier in the 15th century, the Crimean Tatars founded an independent Crimean Khanate under Hacı I Giray, a descendant of Genghis Khan.

The Crimean Tatars controlled the steppes that stretched from the Kuban to the Dniester River, but they were unable to take control over the commercial Genoese towns called Gazaria (Genoese colonies), which had been under Genoese control since 1357. After the conquest of Constantinople, Genoese communications were disrupted, and when the Crimean Tatars asked for help from the Ottomans, they responded with an invasion of the Genoese towns, led by Gedik Ahmed Pasha in 1475, bringing Kaffa and the other trading towns under their control. After the capture of the Genoese towns, the Ottoman Sultan held Meñli I Giray captive, later releasing him in return for accepting Ottoman suzerainty over the Crimean Khans and allowing them to rule as tributary princes of the Ottoman Empire. However, the Crimean Khans still had a large amount of autonomy from the Ottoman Empire, while the Ottomans directly controlled the southern coast.

An Ottoman army under Gedik Ahmed Pasha invaded Italy in 1480, capturing Otranto. Because of lack of food, Gedik Ahmed Pasha returned with most of his troops to Albania, leaving a garrison of 800 infantry and 500 cavalry behind to defend Otranto in Italy. It was assumed he would return after the winter. Since it was only 28 years after the fall of Constantinople, there was some fear that Rome would suffer the same fate. Plans were made for the Pope and citizens of Rome to evacuate the city. Pope Sixtus IV repeated his 1481 call for a crusade. Several Italian city-states, Hungary, and France responded positively to the appeal. The Republic of Venice did not, however, as it had signed an expensive peace treaty with the Ottomans in 1479.

In 1481 king Ferdinand I of Naples raised an army to be led by his son Alphonso II of Naples. A contingent of troops was provided by king Matthias Corvinus of Hungary. The city was besieged starting 1 May 1481. After the death of Mehmed on 3 May, ensuing quarrels about his succession possibly prevented the Ottomans the sending reinforcements to Otranto. So the Turkish occupation of Otranto ended by negotiation with the Christian forces, permitting the Turks to withdraw to Albania, and Otranto was retaken by Papal forces in 1481.

After conquering Constantinople, when Mehmed II finally entered the city through what is now known as the Topkapi Gate, he immediately rode his horse to the Hagia Sophia, where he ordered the building to be protected. He ordered that an imam meet him there in order to chant the Muslim Creed: "I testify that there is no god but God. I testify that Muhammad is the messenger of Allah." The Orthodox cathedral was transformed into a Muslim mosque through a charitable trust, solidifying Islamic rule in Constantinople.

Mehmed’s main concern with Constantinople was with rebuilding the city’s defenses and repopulation. Building projects were commenced immediately after the conquest, which included the repair of the walls, construction of the citadel, and building a new palace. To encourage the return of the Greeks and the Genoese who had fled from Galata, the trading quarter of the city, he returned their houses and provided them with guarantees of safety. Mehmed issued orders across his empire that Muslims, Christians, and Jews should resettle in the City demanding that five thousand households needed to be transferred to Constantinople by September. From all over the Islamic empire, prisoners of war and deported people were sent to the city; these people were called "Sürgün" in Turkish (Greek: σουργούνιδες sourgounides; "immigrants").

Mehmed restored the Ecumenical Orthodox Patriarchate (6 January 1454) and established a Jewish Grand Rabbinate (Ḥakham Bashi) and the prestigious Armenian Patriarchate of Constantinople in the capital, as part of millet system. In addition he founded, and encouraged his viziers to found, a number of Muslim institutions and commercial installations in the main districts of Constantinople, such as the Rum Mehmed Pasha Mosque built by the Grand Vizier Rum Mehmed Pasha. From these nuclei, the metropolis developed rapidly. According to a survey carried out in 1478, there were then in Constantinople and neighboring Galata 16,324 households, 3,927 shops, and an estimated population of 80,000. The population was about 60% Muslim, 20% Christian, and 10% Jewish.

By the end of his reign, Mehmed's ambitious rebuilding program had changed the city into a thriving imperial capital. According to the contemporary Ottoman historian Neşri, "Sultan Mehmed created all of Istanbul". Fifty years later, Constantinople had again become the largest city in Europe.

Two centuries later, the well-known Ottoman itinerant Evliya Çelebi gave a list of groups introduced into the city with their respective origins. Even today, many quarters of Istanbul, such as Aksaray and Çarşamba, bear the names of the places of origin of their inhabitants. However, many people escaped again from the city, and there were several outbreaks of plague, so that in 1459 Mehmed allowed the deported Greeks to come back to the city. This measure apparently had no great success, since French voyager Pierre Gilles writes in the middle of the 16th century that the Greek population of Constantinople was unable to name any of the ancient Byzantine churches that had been transformed into mosques or abandoned. This shows that the population substitution had been total.

Mehmed II introduced the word Politics into Arabic “Siyasah” from a book he published and claimed to be the collection of Politics doctrines of the Byzantine Caesars before him.

He gathered Italian artists, humanists and Greek scholars at his court, allowed the Byzantine Church to continue functioning, ordered the patriarch Gennadius to translate Christian doctrine into Turkish, and called Gentile Bellini from Venice to paint his portrait as well as Venetian frescoes that are vanished today.

He collected in his palace a library which included works in Greek, Persian and Latin. Mehmed invited Muslim scientists and astronomers such as Ali Qushji and artists to his court in Constantinople, started a University, built mosques (for example, the Fatih Mosque), waterways, and Istanbul's Topkapı Palace and the Tiled Kiosk. Around the grand mosque that he constructed, he erected eight madrasas, which, for nearly a century, kept their rank as the highest teaching institutions of the Islamic sciences in the empire.

Mehmed II allowed his subjects a considerable degree of religious freedom, provided they were obedient to his rule. After his conquest of Bosnia in 1463 he issued the Ahdname of Milodraž to the Bosnian Franciscans, granting them freedom to move freely within the Empire, offer worship in their churches and monasteries, and to practice their religion free from official and unofficial persecution, insult or disturbance. However, his standing army was recruited from the Devshirme, a group that took first-born Christian subjects at a young age and destined them for the sultan's court. The less able, but physically strong, were instead put into the army or the sultan's personal guard, the Janissaries.

Within Constantinople, Mehmed established a millet or an autonomous religious community, and appointed the former Patriarch Gennadius Scholarius as religious leader for the Orthodox Christians of the city. His authority extended to all Ottoman Orthodox Christians, and this excluded the Genoese and Venetian settlements in the suburbs, and excluded Muslim and Jewish settlers entirely. This method allowed for an indirect rule of the Christian Byzantines and allowed the occupants to feel relatively autonomous even as Mehmed II began the Turkish remodeling of the city, turning it into the Turkish capital, which it remained until the 1920s.

Mehmed the Conqueror consolidated power by building his imperial court, the divan, with officials who would be solely loyal to him and allow him greater autonomy and authority. Under previous sultans the divan had been filled with members of aristocratic families that sometimes had other interests and loyalties than that of the sultan. Mehmed the Conqueror transitioned the empire away from the Ghazi mentality that emphasizes ancient traditions and ceremonies in governance and moved the empire towards a centralized bureaucracy largely made of officials of devşirme background.

Additionally, Mehmed the Conqueror took the step of converting the religious scholars who were part of the Ottoman madrasas into salaried employees of the Ottoman bureaucracy who were loyal to him. This centralization was possible and formalized through a kanunname, issued during 1477-1481, which for the first time listed the chief officials in the Ottoman government, their roles and responsibilities, salaries, protocol and punishments, as well as how they related to each other and the sultan.

Once Mehmed had created an Ottoman bureaucracy and transformed the empire from a frontier society to a centralized government, he took care to appoint officials who would help him implement his agenda. His first grand vizier was Zaganos Pasha, who was of devşirme background as opposed to an aristocrat, and Zaganos Pasha’s successor, Mahmud Pasha Angelović, was also of devşirme background.

Mehmed was the first sultan who was able to codify and implement kanunname solely based on his own independent authority.

Additionally, Mehmed was able to later implement kanunname that went again previous tradition or precedent. This was monumental in an empire that was so steeped in tradition and could be slow to change or adapt. Having viziers and other officials who were loyal to Mehmed was an essential part of this government because he transferred more power to the viziers than previous sultans had. He delegated significant powers and functions of government to his viziers as part of his new policy of imperial seclusions. A wall was built around the palace as an element of the more closed era, and unlike previous sultans Mehmed was no longer accessible to the public or even lower officials. His viziers directed the military and met foreign ambassadors, two essential parts of governing especially with his numerous military campaigns.

On his accession as conqueror of Constantinople, aged 21, Mehmed was reputed to be fluent in several languages, including Turkish, Serbian, Arabic, Persian, Greek and Latin.

At times, he assembled the Ulama, or learned Muslim teachers, and caused them to discuss theological problems in his presence. During his reign, mathematics, astronomy, and Muslim theology reached their highest level among the Ottomans. His social circle included a number of humanists and sages such as Ciriaco de’ Pizzicolli of Ancona, Benedetto Dei of Florence and Michael Critobulus of Imbros, who mentions Mehmed as a Philhellene thanks to his interest in Grecian antiquities and relics. It was on his orders that the Parthenon and other Athenian monuments were spared destruction. Besides, Mehmed II himself was a poet writing under the name "Avni" (the helper, the helpful one) and he left a classical diwan (poetry).