Due to its strategic significance, the historical Armenian homelands of Western Armenia and Eastern Armenia were constantly fought over and passed back and forth between Safavid Persia and the Ottomans. For example, at the height of the Ottoman-Persian wars, Yerevan changed hands fourteen times between 1513 and 1737. Greater Armenia was annexed in the early 16th century by Shah Ismail I. Following the Peace of Amasya of 1555, Western Armenia fell into the neighbouring Ottoman hands, while Eastern Armenia stayed part of Safavid Iran, until the 19th century.

Armenians preserved their culture, history, and language through the course of time, largely thanks to their distinct religious identity among the neighboring Turks and Kurds. Like the Greek Orthodox and Jewish minorities of the Ottoman Empire, they constituted a distinct millet, led by the Armenian Patriarch of Constantinople. Under Ottoman rule, Armenians formed three distinct millets: Armenian Orthodox Gregorians, Armenian Catholics, and Armenian Protestants (in the 19th century).

After many centuries of Turkish rule in Anatolia and Armenia (at first by the Seljuks, then a variety of Anatolian beyliks and finally the Ottomans), the centres with a high concentration of Armenians lost their geographic continuity (parts of Van, Bitlis, and Kharput vilayets). Over the centuries, tribes of Turks and Kurds settled into Anatolia and Armenia, which was left severely depopulated by a slew of devastating events such as the Byzantine-Persian Wars, Byzantine-Arab Wars, Turkish migration, Mongol Invasions and finally the bloody campaigns of Tamerlane.

In addition, there were the century-long Ottoman-Persian Wars between the rival empires, the battlegrounds of which ranged over Western Armenia (therefore large parts of the native lands of the Armenians), causing the region and its peoples to be passed between the Ottomans and Persians numerous times. The wars between the arch-rivals started from the early 16th century and lasted till well into the 19th century, having disastrous effects for the native inhabitants of these regions, including the Armenians of Western Armenia. There were also significant communities in parts of Trebizond and Ankara vilayets bordering Six vilayets (such as in Kayseri). After the Ottoman conquests many Armenians also moved west and settled in Anatolia, in large and prosperous Ottoman cities like Istanbul and Izmir.