The Eastern provinces of the fledgling Sasanian Empire bordered on the land of the Kushans and the land of the Sakas (roughly today's Turkmenistan, Afghanistan and Pakistan). The military operations of Shapur's father Ardashir I had led to the local Kushan and Saka kings offering tribute, and satisfied by this show of submission, Ardashir seems to have refrained from occupying their territories.

Soon after the death of his father in 241 CE, Shapur felt the need to cut short the campaign they had started in Roman Syria, and reassert Sasanian authority in the East, perhaps because the Kushan and Saka kings were lax in abiding to their tributary status. However, he first had to fight "The Medes of the Mountains" - as we will see possibly in the mountain range of Gilan on the Caspian coast - and after subjugating them, he appointed his son Bahram (the later Bahram I) as their king. He then marched to the East and annexed most of the land of the Kushans, and appointing his son Narseh as Sakanshah - king of the Sakas - in Sistan. In 242 CE, Shapur conquered Khwarezm.