The Parthian Empire, weakened by internal strife and wars with Rome, was soon to be followed by the Sasanian Empire. Indeed, shortly afterward, Ardashir I, the local Iranian ruler of Persis (modern Fars Province, Iran) from Istakhr began subjugating the surrounding territories in defiance of Arsacid rule. He confronted Artabanus IV at the Battle of Hormozdgān on 28 April 224 CE, perhaps at a site near Isfahan, defeating him and establishing the Sasanian Empire. There is evidence, however, that suggests Vologases VI continued to mint coins at Seleucia as late as 228 CE.

The Sassanians would not only assume Parthia's legacy as Rome's Persian nemesis, but they would also attempt to restore the boundaries of the Achaemenid Empire by briefly conquering the Levant, Anatolia, and Egypt from the Eastern Roman Empire during the reign of Khosrau II (r. 590–628 CE). However, they would lose these territories to Heraclius—the last Roman emperor before the Arab conquests. Nevertheless, for a period of more than 400 years, they succeeded the Parthian realm as Rome's principal rival.