In 113, the Roman emperor Trajan (r. 98–117) launched a war against Rome's long-time eastern rival, the Parthian Empire.

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.

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.

[9] For the remainder of its existence, the province would remain a bone of contention between the Romans and their eastern neighbors, suffering heavily in the recurrent Roman–Persian Wars.

In the turmoil that followed the Year of the Six Emperors, in 239–243, Ardashir I (r. 224–241), the founder of the new Sassanid Empire which replaced the moribund Parthians, attacked and overran the area, but it was recovered by Timesitheus before his death in 243.

Nisibis and Singara, along with the territory in Adiabene conquered by Diocletian were lost after the debacle of Julian's Persian expedition in 363, and the capital was transferred to Amida, while the seat of the military commander, the dux Mesopotamiae, was located at Constantina.