Confrontations with nomadic tribes from Central Asia soon started to occur. Ammianus Marcellinus reports that in 356 CE, Shapur II was taking his winter quarters on his eastern borders, "repelling the hostilities of the bordering tribes" of the Chionites and the Euseni (Kushans), finally making a treaty of alliance with the Chionites and the Gelani in 358 CE.

From around 360 CE however, during his reign, the Sasanids lost the control of Bactria to invaders from the north, first the Kidarites, then the Hephthalites and the Alchon Huns, who would follow up with the invasion of India.