The moon rises at a predestined angle and awakens the sleeping Dr. Phibes three years later. To his dismay, he finds his house has been demolished and his papyrus scrolls stolen, the scrolls he needs to find the Pharoah's Tomb in Egypt, where the River of Life flows. After identifying the source of the papyrus theft, he packs and leaves for Egypt with his assistant Vulnavia, still intent upon awakening his dead wife Victoria. The parties responsible for the theft of Phibes' scrolls suffer an attrition problem as Inspector Trout chases him across the world.

Three years after Dr. Anton Phibes seals himself inside a secret underground crypt with his beloved, dead wife Victoria, and subsequently enters a state of suspended animation, the moon comes into conjunction with the planets as depicted on the crypt, triggering blood to flow into Phibes's veins and bring him back to life. Years earlier, Phibes had prepared a shrine within a warren of caves leading to a pharaoh's tomb and sarcophagus that sits above the gates to a river containing the elixir of life. Now determined to resurrect Victoria by immersing her in the waters of the river, Phibes summons his loyal assistant Vulnavia to embark with him on the journey to Egypt. However, when Vulnavia and Phibes ascend to the first floor of his mansion, they discover the edifice has been demolished and the papyrus map pinpointing the location of the tomb stolen. Phibes suspects that Darius Biederbeck, a scientist who also is searching for the elixir of life, has stolen the map. Meanwhile, at Biederbeck's house, the scientist shows archaeologist Harry Ambrose the map and tells him about the river. Biederbeck then departs with his mistress, Diana, and Ambrose to attend a party, leaving behind his bodyguard Chen to guard the map. As Chen plays billiards, Vulnavia unleashes several snakes on the floor. After one bites Chen, he rushes to phone for help, but when he picks up the receiver, a spike in the shape of a golden snake pierces his skull and kills him, after which Phibes retrieves the map. Inspector Trout and Superintendent Waverley are summoned from Scotland Yard to investigate the murder, but are perplexed when Biederbeck's expresses more concern over the missing map than his murdered bodyguard. Phibes and Vulnavia then set sail for Egypt, with Victoria, tucked safely into her customized coffin, stored in the ship's hold. Unknown to Phibes, also onboard are Biederbeck, Diana and Ambrose. Dispatched to the ship's hold to retrieve Biederbeck's model of the mountain in which the sarcophagus is hidden, Ambrose spots Victoria's elaborate coffin and next to it, Phibes's mechanical musicians. Phibes, who has come to the hold to visit Victoria, kills Ambrose, stuffs his body in a giant model of a gin bottle and tosses it overboard. After the bottle washes up on the shore, Trout and Waverley question Lombardo, the ocean liner's shipping agent. When Lombardo recalls that one of the passengers on Ambrose's boat requested an organ for his room, Trout, who had pursued Phibes several years ago, begins to suspect that Phibes is involved. Later, Ambrose's cousin comes to see Waverley about her relative's death and points to the location in Egypt where Ambrose and Beiderbeck were headed. Trout and Waverly then set sail for Egypt while Biederbeck and Diana, who have already arrived, drive to the base camp where they are to meet Hackett, Baker, Shavers and Stewart, men hired by Biederbeck to help with the expedition. Shavers has gone on ahead to the caves, and when he finds the hidden entrance to the tomb, an eagle swoops down and claws him to death, then consumes him for dinner. Meanwhile, comfortably ensconced in the tomb below the caves, Phibes shows Vulnavia the hidden room which will flood once the waters rise, creating a tributary that will float them through locked gates to the river of life. The key that will open the gates is concealed within the sarcophagus. Phibes then stows Victoria's coffin within the sarcophagus, waiting for the full moon, which will trigger the flow of water. Soon after, Vulnavia seduces Stewart into following her, and after enticing him into a trap, leaves him behind with a nest of scorpions that sting him to death. While searching the caves, Biederbeck finds the sarcophagus, and after conveying it back to camp, removes the hidden key. After docking, Trout and Waverley drive into the desert, where they find Stewart's body, then spot smoke coming from Biederbeck's campfire and drive there. Realizing that Phibes is behind the grisly murders, Biederbeck instructs Baker to sleep in the sarcophagus tent. As Baker dozes on his cot, Vulnavia connects it to a vice, then squashes him to death, after which Phibes reclaims the sarcophagus and finds the key missing. The next day, Biederbeck tells Hackett to drive Diana to safety, and as they traverse the desert in a truck, Hackett sees a British flag at the crest of a sand dune in the distance. Hearing bagpipes, Hackett thinks that it is a friendly platoon and goes to ask for help, leaving Diana alone in the truck. Upon reaching the sand dune, Hackett finds Phibes's mechanical musicians, and realizing that Diana is in danger, hurries back to the truck, which is now empty. After he turns the ignition key, sand blasts out of the dashboard, burnishing the flesh from Hackett's face. Fearing for Diana's life, Biederbeck runs into the cave to save her, and as Trout and Waverley try to follow, a door slides shut in front of them, blocking their admission. Coming face to face with his nemesis, Phibes demands that Biederbeck give him the key, warning that it is the only thing that can save Diana. Biederbeck finds the unconscious Diana encased in chicken wire on a platform resting on the floor of the hidden room. As the waters begin to rise, the platform is raised up toward the ceiling which bears metal snakeheads with forked spears spewing from their mouths. Phibes then informs him that only by unlocking the gates with the key will the water drain into the river of life, allowing Diana's platform to recede out of danger. Biederbeck confides that for one hundred years his youth has been sustained by the elixir of life. He has drained the last drops in his bottle and, handing the key over to Phibes, begs that he be allowed to join him on his journey. Once Phibes unlocks the gates, the water empties from Diana's pool, removing her from danger. The door to the temple then slides open, and Trout and Waverley arrive just in time to watch Vulnavia, Victoria and Phibes floating on a raft to the other side of the gates while Biederbeck plunges into the water, pleading to go along with them. As the gates swing shut, blocking Biederbeck's ingress, Biederbeck degenerates into an old man and dies.