In Thebes, Egypt, 1,290 BC, high priest Imhotep engaged in an affair with Anck-su-Namun, the mistress of Pharaoh Seti I. When the Pharaoh discovered their tryst, Imhotep and Anck-su-Namun murdered the monarch. As Seti's guards arrive, Imhotep fled while Anck-su-Namun killed herself, intending for Imhotep to resurrect her. After Anck-su-Namun's burial, Imhotep and his priests stole her corpse and travelled to Hamunaptra, the city of the dead, where they began the resurrection ceremony. However, they were intercepted by Seti's guards before the ritual could be completed, and Anck-su-Namun's soul was sent back to the Underworld. Imhotep's priests were mummified alive; Imhotep was sentenced to immortal agony, condemned to suffer the Hom Dai curse, buried alive with flesh-eating scarab beetles. He was buried under high security, sealed away in a sarcophagus at the feet of a statue of the Egyptian god Anubis, and kept under strict surveillance by warriors known as the Medjai; for all humanity would be doomed should he resurface.
Over 3000 years later in 1926, when Sora and friends arrive and meet Evelyn, a Cairo librarian and aspiring Egyptologist, her brother, Jonathan presents them an intricate box and map which Jonathan says he found in Thebes. After the pair discover the map leads to Hamunaptra, Jonathan reveals he stole it from an American adventurer named Rick O'Connell, currently in prison. Evelyn and Jonathan visit Rick; he tells them that he knows the location of the city because his unit of the French Foreign Legion found the location years ago. He makes a deal with Evelyn to reveal the location of Hamunaptra, in exchange for Evelyn saving Rick from being hanged.
When Sora and friends arrived in the docks, Rick leads them and Evelyn and Jonathan's small expedition to the city, where the group encounters a band of American treasure hunters led by the famed British Egyptologist Dr. Allen Chamberlain and guided by Beni Gabor, a cowardly former comrade of Rick. Shortly after reaching Hamunaptra, the expeditions are attacked by the Medjai, led by the warrior Ardeth Bay. Ardeth warns them of the evil buried in the city, but despite his warning, the two expeditions continue to excavate in separate portions of the city. Evelyn searches for the Book of Amun-Ra, a solid gold book reportedly capable of taking life away, but comes across the remains of Imhotep instead. The team of Americans, meanwhile, discover a box containing the black Book of the Dead, accompanied by canopic jars carrying Anck-su-Namun's preserved organs; Chamberlain steals the Book of the Dead while each of the Americans pockets a jar as loot. Before opening the box, Chamberlain reads an engraving saying that any and all who open the box are cursed if Imhotep is awakened. The men ignore the warnings, but Beni refuses to assist them, and flees. Not far away, Jafar, Maleficent, Hades, Dr. Nefarious, Gaston, Lawrence (Robot), Mother Gothel, Hans, Shenzi, Banzai, Ed, King Candy, Captain Gutt, Uka Uka, Dr. Facilier, Scar, Ursula, Oogie Boogie, The Grand Duke of Owls, Malefor, Dr. Neo Cortex, Erol and Shan Yu discover that Sora and his other pals had found the mummy and plot to awaken it so that they can unleash the power of darkness from the keyhole to this world.
At night, Evelyn takes the Book of the Dead and reads a page aloud, accidentally awakening Imhotep. The expeditions flee to Cairo, but Imhotep follows them with the help of Beni and the villains, who bargain with Imhotep; the antagonist promises not to kill Beni in return. Imhotep absorbs the life from the American expedition, returning to full strength. Seeking a way to stop Imhotep, Rick, Evelyn and Jonathan meet Ardeth at a museum. After Evelyn reveals that Imhotep referred to her as Anck-su-Namun in Hamunaptra, Ardeth and museum curator Terrence Bay hypothesize that Imhotep wants to resurrect his lover again and will do so by sacrificing Evelyn. Evelyn muses that if the Book of the Dead brought Imhotep back to life, the Book of Amun-Ra can kill him again. After discovering the location of the Book, Imhotep corners the group with an army of slaves. Evelyn agrees to accompany Imhotep if he spares the lives of the rest of the group. Imhotep goes back on his word and the villains kidnap Jessie and leave his slaves to kill the group anyway. However, Rick discovers an entrance to the sewers and they escape. Terrence sacrifices himself to buy the others time to escape.
Imhotep, Evelyn, Beni and the villains return to Hamunaptra, pursued by Rick, Jonathan, Ardeth, Sora, Woody and pals. The battle commences as Maleficent, Jafar, and Ursula combine their magic to become their monstrous final forms, while Hans summons enough dark magic to transform himself into Legion. Evelyn and Jessie are rescued after an intense battle with Imhotep's mummified priests and the Seekers, as Evy reads from the Book of Amun-Ra. Imhotep becomes mortal, and Rick stabs him, forcing him into the River of Death. Rapidly decaying, Imhotep leaves the world of the living, vowing revenge with the same words he carved into his sarcophagus, Death is only the beginning. The Seekers of Darkness, repulsed by the overwhelming light exuding from the Book of Amun-Ra, flee into a Dark Corridor Portal, though not before Maleficent vows that gathering of the 7 Guardians and 13 Shadows will soon be nigh. While looting treasure from the pyramid, Beni accidentally sets off an ancient booby trap and is trapped by a swarm of flesh-eating scarabs as Hamunaptra collapses into the sand. The heroes escape, although they lose the Book of Amun-Ra in the process. Rick, Jonathan and Evelyn ride off into the sunset on a pair of camels laden with Beni's treasure.