The Mamelukes moved all trade to Egypt, making Syria a quiet backwater. Even so, invaders still came; Tamerlane in 1400–01 sacked Aleppo, Hamah, and Damascus. Meanwhile, the Ottoman Turks had become rulers of the former Seljuk and Byzantine domains. In 1516 they defeated the Mamelukes near Aleppo and annexed Syria and Palestine. Bypassed by the new sea route around Africa and generally ignored by its Ottoman rulers, Syria stagnated for the next four centuries. Lebanon became largely autonomous under chiefs of the Druse religious sect.

European traders, however, revived trade over the land route to the east by establishing posts in Aleppo and other Syrian cities. They were followed by Christian missionaries; in 1740 France assumed responsibility for pilgrims to the Holy Land. Egypt, nominally an Ottoman domain, seized Palestine and Syria in 1831, but the European powers forced it to withdraw. Friction between the Druses and Christians led in 1860 to the murder of some 10,000 Christians. France intervened, and Lebanon was officially separated from Syria.