According to Justin, Mithridates II avenged the death of his "parents or ancestors" (ultor iniuriae parentum), which indicates that he fought and defeated the Tocharians, who had killed Artabanus I and Phraates II. Mithridates II also reconquered western Bactria from the Scythians. Parthian coinage and scattered reports imply that Mithridates II ruled Bactra, Kampyrtepa, and Termez, which means that he had reconquered the very lands that been conquered by his namesake Mithridates I (r. 171 – 132 BCE). Control over the middle Amu Darya including Amul was vital for the Parthians, in order to thwart incursions by nomads from Transoxiana, particularly from Sogdia. Parthian coins continued to be minted in western Bactria and in the middle Amu Darya until the reign of Gotarzes II (r. 40–51 CE).

Nomadic invasions had also reached the eastern Parthian province of Drangiana, where strong Saka dominions had been established, thus giving the rise to the name Sakastan ("land of the Saka"). These nomads had probably migrated to the area due to the pressure that Artabanus I and Mithridates II had been putting against them in the north. Sometime between 124 and 115 BCE, Mithridates II sent an army led by a general of the House of Suren to recapture to the region. After Sakastan was incorporated back into the Parthian realm, Mithridates II rewarded the region to the Surenid general as his fiefdom. The eastern extent of the Parthian Empire under Mithridates II reached as far as Arachosia.