In 1921, an archaeological expedition led by Sir Joseph Whemple (Arthur Byron) finds the mummy of an ancient Egyptian high priest named Imhotep (Boris Karloff). An inspection of the mummy by Whemple's friend Dr. Muller (Edward Van Sloan) reveals that the viscera were not removed, and from the signs of struggling Muller deduces that although Imhotep had been wrapped like a traditional mummy, he had been buried alive. Also buried with Imhotep is a casket with a curse on it. Despite Muller's warning, Sir Joseph's assistant Ralph Norton (Bramwell Fletcher) opens it and finds an ancient life-giving scroll, the "Scroll of Thoth". He translates the symbols and then reads the words aloud. Imhotep rises, the sight of which snaps Norton's mind and causes him to laugh hysterically as the Mummy shuffles off with the scroll.

Ten years later, Imhotep has assimilated into a mysterious Egyptian historian named Ardeth Bey. He calls upon Sir Joseph's son Frank (David Manners) and Professor Pearson (Leonard Mudie) and shows them where to dig to find the tomb of the princess Anck-su-namun. After locating the tomb, the archaeologists present its treasures to the Cairo Museum, and Ardeth Bey disappears.

Ardeth soon encounters Helen Grosvenor (Zita Johann), a half-Egyptian woman bearing a striking resemblance to the princess. He reveals to her that his horrific death was punishment for sacrilege: attempting to resurrect his forbidden lover, Princess Anck-su-namun. Believing her to be Anck-su-namun's reincarnation, he attempts to kill her, with the intention of mummifying her, resurrecting her, and finally making her his immortal bride. Helen is rescued when she remembers her ancestral past life and prays to the goddess Isis to come to her aid. The statue of Isis raises its arm and emits a flash that sets the Scroll of Thoth on fire. This breaks the spell that had given Imhotep his immortality, causing him to crumble to dust. At the urging of Dr. Muller, Frank calls Helen back to the world of the living while the Scroll of Thoth continues to burn.