The Ottoman–Mamluk War of 1516–1517 was the second major conflict between the Egypt-based Mamluk Sultanate and the Ottoman Empire, which led to the fall of the Mamluk Sultanate and the incorporation of the Levant, Egypt, and the Hejaz as provinces of the Ottoman Empire.^[26] The war transformed the Ottoman Empire from a realm at the margins of the Islamic world, mainly located in Anatolia and the Balkans, to a huge empire encompassing much of the traditional lands of Islam, including the cities of Mecca, Cairo, Damascus, and Aleppo. Despite this expansion, the seat of the empire's political power remained in Constantinople.^[27]

The relationship between the Ottomans and the Mamluks had been adversarial since the Fall of Constantinople to the Ottomans in 1453; both states vied for control of the spice trade, and the Ottomans aspired to eventually take control of the Holy Cities of Islam.^[28] An earlier conflict, which lasted from 1485 to 1491, had led to a stalemate. By 1516, the Ottomans were free from other concerns—Sultan Selim I had just vanquished the Safavid Persians at the Battle of Chaldiran in 1514—and turned their full might against the Mamluks, who ruled in Syria and Egypt, to complete the Ottoman conquest of the Middle East.

Both the Ottomans and Mamluks assembled 60,000 soldiers. However only 15,000 Mamluk soldiers were trained warriors, the rest were mere conscripts who did not even know how to fire a musket. As a result, most of the Mamluks fled, avoided the front lines, and even committed suicide. In addition, as had happened with the Safavids in the Battle of Chaldiran, the blasts of the Ottoman cannons and guns scared the Mamluk horses which raced uncontrollably in every direction.

The conquest of the Mamluk Empire also opened up the territories of Africa to the Ottomans. During the 16th century, Ottoman power expanded further west of Cairo, along the coasts of northern Africa. The corsair Hayreddin Barbarossa established a base in Algeria, and later accomplished the Conquest of Tunis in 1534.^[27] The conquest of the Mamluks was the largest military venture any Ottoman Sultan had ever attempted. In addition, the conquest put the Ottomans in control of two of the largest cities in the world at the time- Constantinople and Cairo. The conquest of Egypt proved extremely profitable for the empire as it produced more tax revenue than any other Ottoman territory and supplied about 25% of all food consumed. However, Mecca and Medina were the most important of all the cities conquered since it officially made Selim and his descendants the Caliphs of the entire Muslim world until the early 20th century.

Following his capture in Cairo, Caliph Al-Mutawakkil III was brought to Constantinople, where he eventually ceded his office as caliph to Selim's successor, Suleiman the Magnificent. This established the Ottoman Caliphate, with the sultan as its head, thus transferring religious authority from Cairo to the Ottoman throne.