In 1290 BC, high priest Imhotep engages in an affair with Anck-su-namun, the mistress of Pharaoh Seti I of Egypt. When the Pharaoh discovers the affair, Imhotep and Anck-su-namun murder him. In retaliation, Imhotep is cursed with eternal damnation and buried alive, his tomb cursed so that if he is ever awakened, he will bring with him the ten plagues of Egypt. Fast forward to the 1920s, Evelyn, a librarian and aspiring Egyptologist, discovers a map to Hamunaptra, the city of the dead. Alongside her hapless brother Jonathan, they convince American adventurer Rick O'Connell to lead them to the ancient city.

Once at Hamunaptra, the group encounters a rival expedition and inadvertently awakens a dormant and malevolent force. Meanwhile, encounters with ancient booby traps and the discovery of Imhotep's sarcophagus lead to the realization that there is more at stake than just lost treasure. The expeditions must confront the consequences of their actions as dark forces stir and ancient myth begins to become terrifying reality.