Mesopotamia was the name of a Roman province, initially a short-lived creation of the Roman emperor Trajan in 116–117 and then re-established by Emperor Septimius Severus in c. 198. Control of the province was subsequently fought over between the Roman and the Sassanian empires until the Muslim conquests of the 7th century.

In 113, the Roman emperor Trajan (r. 98–117) launched a war against Rome's long-time eastern rival, the Parthian Empire. In 114, he conquered Armenia, which was made into a province, and by the end of 115, he had conquered northern Mesopotamia. This too was organized as a province in early 116, when coins were minted to celebrate the fact.

Later in the same year, Trajan marched into central and southern Mesopotamia (enlarging and completing the province of Mesopotamia) and across the river Tigris to Adiabene, which he annexed into another Roman province, Assyria. But he did not stop there. In the last months of 116, he captured the Persian city of Susa and deposed the Parthian king Osroes I, putting his own puppet ruler Parthamaspates on the Parthian throne. Never again would the Roman Empire advance so far to the east.

As soon as Trajan died, however, his successor Hadrian (r. 117–138) relinquished his conquests east of the Euphrates river, which became again the Roman Empire's eastern boundary.

Northern Mesopotamia, including Osroene, came again under Roman control in the expedition of Lucius Verus in 161–166, but were not formally organized into provinces; instead, they were left under local vassal rulers, although Roman garrisons were maintained, notably at Nisibis.

This control was threatened in 195, during the civil war between Septimius Severus (r. 193–211) and the usurper Pescennius Niger, when rebellions broke out in the area, and Nisibis was besieged. Severus quickly restored order and organized Osroene as a full province.

Next, Severus embarked on a war against Parthia, which he concluded successfully with the sack of the Parthian capital Ctesiphon. In emulation of Trajan, he re-established a province of Mesopotamia in 198, with Nisibis, elevated to the status of a full colonia, as its capital.

Unlike Trajan's province, which encompassed the whole of Roman-occupied Mesopotamia between the Euphrates and Tigris rivers, the new province was limited between the province of Osroene to the south, the Euphrates and Tigris to the north, and the river Chaboras (modern Khabur) to the east.