In 3067 BC, the Scorpion King leads his army to conquer the world. However, his army is defeated and exiled to the desert of Ahm Shere, where his men die of heat exhaustion. After vowing to give Anubis his soul for the power to defeat his enemies, an oasis and pyramid magically form, and the Scorpion King is given a legion of jackal-like warriors. The Army of Anubis sweeps across Egypt, but once their task is finished, Anubis claims the Scorpion King's soul and the army returns to the Underworld.

In 1933, Rick O'Connell and his wife Evelyn explore ancient ruins with their son, Alex, where they find the Bracelet of Anubis. In London, the bracelet locks onto Alex, showing him a vision directing him to Ahm Shere.

Evelyn is captured by an Egyptian cult who resurrect Imhotep with the Book of the Dead; they wish to use his power to defeat the Scorpion King, giving him command of Anubis' army to conquer the world. The cult, led by Baltus Hafez, includes enforcer Lock-Nah and Meela Nais, the reincarnation of Imhotep's love Anck-su-namun. The O'Connells set out to rescue Evelyn, accompanied by her brother Jonathan and the Medjai Ardeth Bay. Jonathan gets his hands on a mysterious golden Scepter of Osiris.

Rick frees Evelyn and flees, but Alex is subsequently kidnapped by Lock-Nah, and forced to travel to Egypt along with the cult. The O'Connells pursue them, along with help from Rick's associate Izzy, a pilot who provides the group with transportation.

The bracelet gives Alex directions to Ahm Shere that Imhotep and the cult follow. At each location, Alex leaves clues for his parents, who follow in Izzy's dirigible. Imhotep uses the Book of the Dead to give Meela the soul of Anck-su-namun, but by doing so he allows Evelyn to unlock the memories of her previous life as Princess Nefertiri, the bracelet's keeper and Pharaoh Seti I's daughter.

At the edge of the Oasis, Imhotep uses his magic to crash the dirigible; Izzy stays behind in hopes of repairing it. By nightfall, the O'Connells infiltrate the cult, but both groups are attacked by pygmy mummies. Rick retrieves Alex while Ardeth Bay kills Lock-Nah. They escape the pygmies, who kill all the cult members except for Baltus, Imhotep and Anck-su-namun.

Rick and Alex eventually make it to the pyramid at dawn, and the bracelet detaches from Alex. Anck-su-namun arrives and kills Evelyn, escaping into the pyramid with Imhotep and Baltus. Rick pursues them. Inside the pyramid, Baltus puts on the bracelet and revives the army. Anubis takes Imhotep's powers, wanting Imhotep to fight as a mortal.

Rick finds Imhotep summoning the Scorpion King and fights him. The Scorpion King, now an enormous monster, interrupts the fight and attacks Rick. At the same time, Ardeth and the Medjai battle Anubis's resurrected army outside. While Rick and the Scorpion King fight, Baltus is killed. Jonathan and Alex steal the "Book of the Dead" from Anck-su-namun and use it to resurrect Evelyn, who confronts Anck-su-namun while Alex and Jonathan go to help Rick.

Rick discovers Jonathan’s scepter is actually a weapon, a spear that can kill the Scorpion King. The Medjai seem to defeat Anubis' army, but realize it was only the vanguard; the full army appears and charges toward them. Rick gets the scepter/spear from Jonathan and kills the Scorpion King, sending him and his army back into the Underworld, which causes the Oasis to begin to destroy itself.

Rick and Imhotep are thrown back and hang above a pit that leads to the underworld. Evelyn risks her life to save Rick, but Anck-su-namun abandons Imhotep, who chooses to let go and fall into the pit, heartbroken. While trying to escape, Anck-su-namun falls into a pit of scorpions and dies. The O'Connells reach the top of the pyramid. Izzy arrives with a modified dirigible and rescues the O'Connells just before the oasis and the pyramid are totally destroyed. They depart into the sunset, with Ardeth Bay saluting them before riding off.

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