In the 3rd century CE, the Parthians were in turn succeeded by the Sassanid dynasty, which ruled Mesopotamia until the 7th-century Islamic invasion. The Sassanids conquered the independent states of Adiabene, Osroene, Hatra and finally Assur during the 3rd century. In the mid-6th century the Persian Empire under the Sassanid dynasty was divided by Khosrow I into four quarters, of which the western one, called Khvārvarān, included most of modern Iraq, and subdivided to provinces of Mishān, Asoristān (Assyria), Adiabene and Lower Media.

Asōristān, Middle Persian "land of Assyria", was the capital province of the Sasanian Empire and was called Dil-ī Ērānshahr, meaning "Heart of Iran".^[46] The city of Ctesiphon served as the capital of both the Parthian and Sasanian Empire, and was for some time the largest city in the world.^[47] The main language spoken by the Assyrian people was Eastern Aramaic which still survives among the Assyrians, with the local Syriac language becoming an important vehicle for Syriac Christianity. Asōristān was largely identical with ancient Mesopotamia.^[48]

There was a substantial influx of Arabs in the Sassanid period. Upper Mesopotamia came to be known as Al-Jazirah in Arabic (meaning "The Island" in reference to the "island" between the Tigris and Euphrates rivers), and Lower Mesopotamia came to be known as ʿIrāq-i ʿArab, meaning "the escarpment of the Arabs". The term Iraq is widely used in the medieval Arabic sources for the area in the center and south of the modern republic as a geographic rather than a political term.

Until 602, the desert frontier of the Persian Empire had been guarded by the Arab Lakhmid kings of Al-Hirah. In that year, Shahanshah Khosrow II Aparviz abolished the Lakhmid kingdom and laid the frontier open to nomad incursions. Farther north, the western quarter was bounded by the Byzantine Empire. The frontier more or less followed the modern Syria-Iraq border and continued northward, passing between Nisibis (modern Nusaybin) as the Sassanian frontier fortress and Dara and Amida (modern Diyarbakır) held by the Byzantines.