While the Parthians regained the territories lost in the west, another threat arose in the east. In 177–176 BCE the nomadic confederation of the Xiongnu dislodged the nomadic Yuezhi from their homelands in what is now Gansu province in Northwest China; the Yuezhi then migrated west into Bactria and displaced the Saka (Scythian) tribes. The Saka were forced to move further west, where they invaded the Parthian Empire's northeastern borders. Mithridates was thus forced to retire to Hyrcania after his conquest of Mesopotamia.

Some of the Saka were enlisted in Phraates' forces against Antiochus. However, they arrived too late to engage in the conflict. When Phraates refused to pay their wages, the Saka revolted, which he tried to put down with the aid of former Seleucid soldiers, yet they too abandoned Phraates and joined sides with the Saka. Phraates II marched against this combined force, but he was killed in battle. The Roman historian Justin reports that his successor Artabanus I (r. c. 128–124 BCE) shared a similar fate fighting nomads in the east.