Shamash-shum-ukin was king of Babylon from 669-648 BC. He was the second son of the Assyrian King Esarhaddon. His elder brother, crown prince Sin-iddina-apla had died in 672, and in his stead the third son Assurbanipal was invested as crown prince and later king of Assyria, while Shamash-shum-ukin remained crown prince of Babylonia. Provincial governors and vassals had to take an oath to accept this and to help the brothers gain their respective thrones in the event of Esarhaddon's death. When Esarhaddon unexpectedly died on a campaign against rebellious Egypt in 669, it was only the decisive action of Naqi'a-Zakutu, widow of Sennacherib that got Assurbanipal on the throne in the face of opposition by court officials and parts of the priesthood. The big statue of Marduk, taken as loot by Sennacherib was returned to Babylon in a solemn procession. The Babylonian territory consisted of Babylon, Borsippa, Kutha and Sippar. While Shamash-shum-ukin was sovereign ruler of the south in theory, Assyria maintained a garrison in Nippur, and some of the provincial governors tried to get into Assyrian favour. Letters by Sin-balassu-iqbi, governor of Ur show how he tried to ingratiate himself with Assurbanipal.

Assurbanipal took an active part in the restoration of sanctuaries in the South, a stela now in London commemorates his help in restoring Esagila (the tower of Babel), another tells of how he restored the Nabu-temple in Borsippa.

In May 652 Shamash-shum-ukin rose in rebellion. The reasons for this are completely unknown, as no Babylonian sources have been preserved. He was joined by Nabu-bel-shumate , king of the sea-country. the Elamites, the Chaldean tribes of the South, the kings of Guti, Amurru and Melukka and tribes from the Arab desert. After two years Babylon and Borsippa were besieged and Elam was beaten. Babylon yielded in June 648 because of starvation. The sources describe cases of cannibalism. Shamash-shum-ukin threw himself into his burning palace, to be remembered by the Greeks in the story of Sardanapal. A certain Kandalu (647-627) is mentioned as king of Babylon after Shamash-shum-ukin, most scholars agree that this is a name taken on by Assurbanipal himself.