He had been placed on the throne after the murder of his brother Artashumara. He was probably quite young at the time and was destined to serve as a figurehead only. But he managed to dispose of the murderer.
At the beginning of his reign, the Hittite King Suppiluliuma I, reconquered Kizzuwatna, then invaded the western part of the Euphrates valley and conquered the Amurru and Nuhašše in Hanilgalbat. According to the Suppiluliuma-Shattiwazza treaty, Suppiluliuma had made a treaty with Artatama, a rival of Tushratta. Nothing is known of Artatama's previous life or connection, if any, to the royal family. The document calls him king of the Hurrians, while Tushratta is given the title of "King of Mitanni", which must have disagreed with Tushratta. Suppiluliuma started to plunder the lands of the west bank of the Euphrates river and he annexed Mount Lebanon. Tushratta threatened to raid beyond the Euphrates if even a single lamb or kid was stolen.
Suppiluliuma then recounts how the land of Isuwa on the upper Euphrates had seceded in the time of his grandfather. Attempts to conquer it failed. In the time of his father, other cities rebelled. Suppiluliumas claims to have defeated them, but the survivors fled to the territory of Isuwa that must have been part of Tushratta's realm. A clause to return fugitives was part of many treaties made at the time, so possibly the harbouring of fugitives by Isuwa formed the pretext for the Hittite invasion. A Hittite army crossed the border, entered Isuwa and returned the fugitives (or deserters or exile governments) to Hittite rule. "I freed the lands which I captured; they dwelt in their places. All the people whom I released rejoined their peoples and Hatti incorporated their territories," Suppiluliuma later boasted.
The Hittite army then marched through various districts towards the Hanilgalbat capital of Washshukanni. Suppiluliumas claims to have plundered the district and to have brought loot, captives, cattle, sheep and horses back to Hatti. He also claims that Tushratta fled, but obviously he failed to capture the capital. While the campaign weakened Tushratta's kingdom, he still held onto his throne.
In a second campaign, the Hittites again crossed the Euphrates and subdued Halab, Mukish, Niya, Arahati, Apina, and Qatna as well as some cities whose names have not been preserved. Charioteers are mentioned among the booty from Arahati, who were brought to Hatti together with all their possessions. While it was common practice to incorporate enemy soldiers in the army, this might point to a Hittite attempt to counter the most potent weapon of the Mitanni, the war-chariots, by building up or strengthening their own chariot forces.
Tushratta had possibly suspected Hittite intentions on his kingdom, for the Amarna letters include several tablets from Tushratta concerning the marriage of his daughter Tadukhipa with Akhenaten, explicitly to solidify an alliance with the Egyptian kingdom (EA 17). However, when Suppiluliumas invaded his kingdom, the Egyptians failed to respond in time -- perhaps because of the sudden death of Akhenaten, and the resulting struggle for control of the Egyptian throne.
According to a treaty later made between Suppiluliuma and Tushratta's brother Shattiwaza, after a third devastating Hittite raid led to the fall of Carchemish, Tushratta was assassinated by a group led by one of his sons. A time of civil war followed which came to an end when Suppiluliuma placed Shattiwaza on the Mitannian throne.