Selim came to the throne in the wake of civil strife in which he, his brother, and their father, Bayezid II, had been involved. Selim eliminated all potential claimants to the sultanate, leaving only his ablest son, Süleyman, as his heir. He then turned eastward, where Ismāʿīl I, founder of the Ṣafavid dynasty in Iran, posed a political and ideological threat by espousing Shīʿism (the second largest branch of Islām) as opposed to the Sunnī Islām of the Ottomans. In addition, the Kizilbash (Turkmen followers of Ismāʿīl) were in open revolt in Anatolia. Selim subdued the Kizilbash and then launched a major campaign against Ismāʿīl, who was severely defeated at the Battle of Chāldirān (Chāldirān, Battle of), on the eastern side of the Euphrates River (Aug. 23, 1514). Selim then turned toward the Anatolian Kurdish and Turkmen principalities, which he incorporated into the Ottoman Empire.

Selim's subjugation of the Dulkadir (Dhū al-Qadr) principality of Elbistan (now in Turkey) brought the Ottomans into conflict with the Mamlūk rulers of Syria and Egypt, who regarded Dulkadir as their protégé. Selim defeated the Mamlūk armies at the battles of Marj Dābiq (north of Aleppo; Aug. 24, 1516) and Raydānīyah (near Cairo; Jan. 22, 1517), thus bringing Syria, Egypt, and Palestine under Ottoman rule. In Cairo the sharif of Mecca presented Selim with the keys to that holy city, a symbolic gesture acknowledging Selim as the leader of the Islāmic world.