Suppiluliumas' military career was almost exclusively devoted to struggles with the kingdom of Mitanni in the east and the reestablishment of a firm Hittite foothold in Syria. After an unsuccessful exploratory raid, he schemed to circumvent the Mitanni defenses in northern Syria by crossing the Euphrates River farther north and approaching its capital, Wassukkani, from the rear. Suppiluliumas' new tactics were successful, and he was able to capture and sack Wassukkani. He then turned south across the Euphrates and secured the allegiance of the Syrian princelings.

Suppiluliumas left his son Telipinus in charge of Syrian affairs and returned to Hattusas to resume religious duties. In the meantime, however, the debilitated Mitanni kingdom underwent a series of upheavals abetted by the renascent Assyrian kingdom, which had long been a tributary of the Mitanni. In the end, Assyria gained its independence, infiltrated Mitanni, and emerged as a new power in the region.

Suppiluliumas immediately returned to Syria, besieging the city of Carchemish. Hittite power was thus consolidated in all of northern Syria, where Suppiluliumas installed his sons Telipinus and Piyassilis as kings of Aleppo and Carchemish. In addition, Suppiluliumas concluded with Mattiwaza, son of the murdered Mitannian king Tushratta, a treaty of mutual assistance. A Mitannian buffer state was set up to shield the Hittite dominions in Syria from the growing Assyrian menace.

Suppiluliumas' preeminent international reputation is shown by an event that occurred during his siege of Carchemish. Ankhesenamen, daughter of the Egyptian king Akhenaton and childless widow of his successor Tutankhamen, wrote to the Hittite king and asked for one of his sons in marriage. Under Egypt's matrilinear succession laws, the new husband was to be the pharaoh. Suppiluliumas agreed and sent one of his sons, who on his way to Egypt was murdered by adversaries of the Queen's plans. This outrage was probably never completely avenged, for Suppiluliumas soon died in a plague brought into central Anatolia by Egyptian prisoners of war.