In 1925 Anton Phibes, a horribly disfigured genius supposedly killed in a car crash, is convinced that his beloved wife died a victim of incompetent doctors, and begins elaborate plans to kill them. Inspector Trout suspects Phibes, but finds little support from Scotland Yard. Eventually Dr. Vesalius, head of the team of doctors that operated on Phibes's wife, begins to believe Trout and aids him in the hunt for Phibes.
Using various highly imaginative methods based on the Ten Plagues that befell Egypt in the Old Testament, and wearing a different amulet from a set of ten Hebrew letters that relate to the Ten Plagues, Phibes kills seven doctors and a nurse with the help of his beautiful and silent female assistant Vulnavia (played by actress Virginia North). He has reserved the final punishment for Dr. Vesalius. He kidnaps the doctor's son and places him on a table on which a container full of acid is waiting to destroy the boy's face. A small key implanted near the boy's heart will free him, but Vesalius must perform the surgery within six minutes to get the key before the acid falls. Vesalius succeeds and instead Vulnavia is sprayed with the acid as the police arrive.
Convinced he has accomplished his vendetta, Phibes retreats to a stone sarcophagus beside the embalmed body of his wife. He drains out his own blood and replaces it with embalming fluid as the coffin's inlaid stone lid slides into place, concealing them both in darkness. Trout and the police arrive and discover that Phibes has mysteriously disappeared. Trout and Vesalius recall that the "final curse" was darkness and they speculate that they will encounter Phibes again.
The Ten Plagues of Egypt Dr. Phibes takes his inspiration for the murders from the Old Testament, the Ten plagues of Egypt. The plagues described in the movie differ slightly from the Biblical account:
7. Beasts: Dr. Whitcombe is impaled by a brass unicorn head
8. Locusts: Nurse Allen is eaten by locusts.
9. Death of the first born: Phibes kidnaps and attempts to kill Dr. Vesalius's son Lem. (This is the final plague in the Biblical account.)
10. Darkness: At the ambiguous ending of the film, Phibes drains the blood from his own body while injecting embalming fluid, apparently joining his wife in death.