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Although Roman Syria had experienced great stability for two centuries, instability remained the norm in Syria during the third century, due to the conflicts with the Persians and internal crises. War with the Persians resumed under Gordian III who briefly reestablished the Abgarid dynasty in Edessa (239–242 ce) in an attempt to create a barrier against the advancing Persians. But he could not prevent the capture and destruction of Hatra (242 ce) even though in 243–244 ce he led a largely victorious campaign that allowed him to retake most of the cities in Mesopotamia and advance toward Ctesiphon. But in the beginning of the year 244 ce, the Roman army was routed at Misichē in the Euphrates valley, leaving the emperor dead and replaced by his praetorian prefect Philip, a native of the province of Arabia. Philip negotiated a costly peace with the Persians and managed to conserve a large part of the province of Mesopotamia.

The peace was broken in 252–253 ce, and the Persian Shapur I took over Dura in 252 ce. Dura was soon after this liberated and then retaken a second time and destroyed in 256 ce. Several North Syrian cities seem to have been pillaged, and fear reigned across all of Syria and into Arabia where cities began to be fortified (Bostra, Adraa). In this political climate, some local personalities, such as Uranius Antoninus in Emesa and Odaenathus in Palmyra, attempted to organize resistance to the Persians. The partial success of this resistance did not prevent a fresh Persian offensive in 259 ce, which affected all of North Syria and forced the emperor Valerian to personally lead the campaign. But Valerian was taken prisoner during a fight near Edessa (late 259 ce) and Antioch was taken.