The Nubian Kingdom to the south took full advantage of the division and political instability. Prior to Piye's Year 20 campaign into Egypt, the previous Nubian ruler, Kashta, had already extended his kingdom's influence over into Thebes when he compelled Shepenupet, the serving Divine Adoratice of Amun and Takelot III's sister, to adopt his own daughter Amenirdis, to be her successor. Piye (Piankhi) marched north and defeated the combined might of several native Egyptian rulers such as Peftjaubast, Osorkon IV of Tanis, Iuput II of Leontopolis and Tefnakht of Sais. He established the Twenty-five Dynasty. In fact, Upper Egypt held out longer against Nubian invaders until being overrun by the armies of their ruler Piankhi all the way to Memphis. Piankhi's brother, Shabaka, marched north to conquer the Delta and reunite Upper and Lower Egypt under the Twenty-fifth Dynasty of Nubian Kings (747-656BC). During this period, there was an artistic and cultural revival.

The Twenty-fifth Dynasty ended when Assyrian armies captured Memphis and attacked Thebes, driving the Nubian pharaoh Tanutamun back to Nubia. He was succeeded first by his brother, Shabaka, and then by his two sons: Shebitku and Taharqa. Taharqa's reign and that of his successor, (his cousin) Tanutamun, were filled with constant conflict with the Assyrians. After a long period of resistance, Thebes was occupied and Memphis was ignored. The Dynasty ended with its rulers centered in the relative backwater of the city of Napata.