Few historical sources remain for the last 30 years of the Assyrian empire. There are no extant inscriptions of Ashurbanipal after 640 bc, and the few surviving inscriptions of his successors contain only vague allusions to political matters. In Babylonia the silence is almost total until 625 bc, when the chronicles resume.

The rapid downfall of the Assyrian empire was formerly attributed to military defeat, although it was never clear how the Medes and the Babylonians alone could have accomplished this. More recent work has established that after 635 a civil war occurred, weakening the empire so that it could no longer stand up against a foreign enemy. Ashurbanipal had twin sons. Ashur-etel-ilani was appointed successor to the throne, but his twin brother Sin-shar-ishkun did not recognize him. The fight between them and their supporters forced the old king to withdraw to Harran, in 632 at the latest, perhaps ruling from there over the western part of the empire until his death in 627. Ashur-etel-ilani governed in Assyria from about 633, but a general, Sin-shum-lisher, soon rebelled against him and proclaimed himself counter-king. Some years later (629?) Sin-shar-ishkun finally succeeded in obtaining the kingship. In Babylonian documents dates can be found for all three kings. To add to the confusion, until 626 there are also dates of Ashurbanipal and a king named Kandalanu. In 626 the Chaldean Nabopolassar (Nabu-apal-uṣur) revolted from Uruk and occupied Babylon. There were several changes in government. King Ashur-etel-ilani was forced to withdraw to the west, where he died sometime after 625.

About the year 626 the Scythians laid waste to Syria and Palestine. In 625 the Medes became united under Cyaxares and began to conquer the Iranian provinces of Assyria. One chronicle relates of wars between Sin-shar-ishkun and Nabopolassar in Babylonia in 625–623. It was not long until the Assyrians were driven out of Babylonia. In 616 the Medes struck against Nineveh, but, according to the Greek historian Herodotus, were driven back by the Scythians. In 615, however, the Medes conquered Arrapkha (Kirkūk), and in 614 they took the old capital of Ashur, looting and destroying the city. Now Cyaxares and Nabopolassar made an alliance for the purpose of dividing Assyria. In 612 Kalakh and Nineveh succumbed to the superior strength of the allies. The revenge taken on the Assyrians was terrible: 200 years later Xenophon found the country still sparsely populated.

Sin-shar-ishkun, king of Assyria, found death in his burning palace. The commander of the Assyrian army in the west crowned himself king in the city of Harran, assuming the name of the founder of the empire, Ashur-uballiṭ II (611–609 bc). Ashur-uballiṭ had to face both the Babylonians and the Medes. They conquered Harran in 610, without, however, destroying the city completely. In 609 the remaining Assyrian troops had to capitulate. With this event Assyria disappeared from history. The great empires that succeeded it learned a great deal from the hated Assyrians, both in the arts and in the organization of their states.