In early 197 Severus left Rome and sailed to the east. He embarked at Brundisium and probably landed at the port of Aegeae in Cilicia, travelling on to Syria by land. He immediately gathered his army and crossed the Euphrates. Abgar IX, titular King of Osroene but essentially only the ruler of Edessa since the annexation of his kingdom as a Roman province, handed over his children as hostages and assisted Severus' expedition by providing archers. King Khosrov I of Armenia also sent hostages, money and gifts.

Severus travelled on to Nisibis, which his general Julius Laetus had prevented from falling into Parthian hands. Afterwards Severus returned to Syria to plan a more ambitious campaign. The following year he led another, more successful campaign against the Parthian Empire, reportedly in retaliation for the support it had given to Pescennius Niger. His legions sacked the Parthian royal city of Ctesiphon and he annexed the northern half of Mesopotamia to the empire; Severus took the title Parthicus Maximus, following the example of Trajan. However, he was unable to capture the fortress of Hatra, even after two lengthy sieges—just like Trajan, who had tried nearly a century before. During his time in the east, though, Severus also expanded the Limes Arabicus, building new fortifications in the Arabian Desert from Basie to Dumatha. These wars led to the Roman acquisition of northern Mesopotamia, as far as the areas around Nisibis and Singara.