The Hephthalites were originally vassals of the Rouran Khaganate but split from their overlords in the early fifth century. The next time they were mentioned was in Persian sources as foes of Yazdegerd II, who from 442, fought 'tribes of the Hephthalites', according to the Armenian Elisee Vardaped.

In 453, Yazdegerd moved his court east to deal with the Hephthalites or related groups.

In 458, a Hephthalite king called Akhshunwar helped the Sasanian Emperor Peroz I gain the Persian throne from his brother. Before his accession to the throne, Peroz had been the Sasanian for Sistan in the far east of the Empire, and therefore had been one of the first to enter into contact with the Hephthalites and request their help.

The Hephthalites may have also helped the Sasanians to eliminate another Hunnic tribe, the Kidarites: by 467, Peroz I, with Hephthalite aid, reportedly managed to capture Balaam and put an end to Kidarite rule in Transoxiana once and for all. The weakened Kidarites had to take refuge in the area of Gandhara.