Jonathan Drake, while attending his brother's funeral, is shocked to find the head of the deceased is missing. When his brother's skull shows up later in a locked cabinet, Drake realizes an ancient curse placed upon his grandfather by a tribe of South American Jivaro Indians is still in effect and that he himself is the probable next victim. That night he is awakened by the approach of an Indian, his lips sewed together with string, and wielding a curare-tipped bamboo knife.
- The movie opens with title and credits shown over a tableau of a burning candle, a skull and an open book on a desk. The highlighted passage from Julius Caesar by Shakespeare appears, "The evil that men do lives after them." Jonathan Drake (Eduard Franz) sits gazing at a shrunken head. A gust of wind blows out the candle and Drake sees three skulls floating in the air, approaching him. He recoils in horror at the apparition. His daughter, Alison (Valerie French) enters the room and lights the candle on the desk. She checks on her father, but he refuses to disclose his troubles. She tells him that Uncle Ken called. She relays the message, "He said he'd seen somebody named Tsantsas." Drake wants clarification on his exact wording because, as he holds up the shrunken head, he tells her, "This is what the Jivaro Indians of Ecuador call a tsantsas." Alison sends Kenneth Drake (Paul Cavanagh) a telegram. He reads it to his servant, Rogers (Lumsden Hare), and asks that the guest room be prepared. A very old and wrinkled hand is seen opening the door to the room. Ken is shocked when he sees a tsantsas or shrunken head swinging outside by the window. He walks over to investigate and encounters Zutai (Paul Wexler), a tall, slender, Indian with long, straight, dark hair and his lips are sewn shut with thin leather strips. Ken recoils from the creature and is stabbed in the neck with a long, sharp knife. Ken collapses and Zutai approaches the body with a basket. He opens the basket and crouches over the body. He is about to sever the head from the body when he is interrupted by the approaching servant, Rogers. Zutai rushes outside from the room as Rogers enters.
A police car arrives at the house as the body of Kenneth Drake is loaded into a funeral coach. Police Lt. Jeff Rowan (Grant Richards) observes the two men loading the body and he rings the doorbell. Rogers answers and tells Rowan that Kenneth Drake past away in the night, natural causes. He tells the policeman, "Dr. Bradford, his personal physician, is still here if you care to talk to him." Rogers escorts the Lieutenant into the living room to see Dr. George Bradford (Howard Wendell). Dr. Emil Zurich (Henry Daniell) is sitting in a chair across from Bradford. He is introduced as a friend of the family and an archaeologist. Rowan extends his hand to greet Zurich, but the man only bows, not reciprocating the handshake. Rowan reviews the death certificate and questions the cause, listed as coronary occlusion. Bradford explains, "There is a long history of cardiovascular failure in the Drake family." He notes that the last three generations of men all died around the age of 60. The subject of the shrunken head comes up, and Zurich claims he is an expert on the subject of tsantsas and the Jivaro Indian culture. Rowan departs. That evening the body of Kenneth Drake is delivered to the house. Zutai returns with his basket. He forces the door and enters the room with the casket. He opens the casket. Jonathan Drake arrives at the house by taxi. He notices the funeral wreath on the door. Rogers tells him of the death of his brother. At the service, Rogers tells Jonathan that it was his heart, but Jonathan questions Bradford if it could have been anything else, but he is told it was a natural death. Jonathan asks why the casket is closed. The funeral director (an uncredited Jonathan Hole) tells Jonathan, "Your brothers face, sir, we thought it better to keep the coffin closed." Jonathan demands it be opened. The funeral director opens the casket. Inside is the headless body of his brother, Kenneth.
At the Zurich home, the doctor tends a fire with a cauldron of boiling liquid inside. He calls Zutai for assistance in retrieving the head of Kenneth Drake. The head is placed in the cauldron. Dr. Bradford attends to Jonathan Drake in bed. Alison asks the doctor how her father is doing. Jonathan feels he was too late to save his brother. Rogers enters the room to inform Alison that Lt. Rowan is waiting to see her. Rowan explains, "The mutilation of your uncle's corpse makes this a criminal case." Rowan is tired of a run around with members of the family. She tells the Lieutenant, "I only know that my father was worried about his brother. And that it had something to do with a tsantsas. Just as I told you." Zutai tends the fire under a bucket of sand. Zurich prepares the head, separating the skull from the skin that covered it. He sews up the skin and Zutai pours the hot sand into the opening at the neck. He places the nearly completed tsantsas of Kenneth on the table, its mouth stitched closed with thin leather strips. Zurich pronounces, "Next will be Jonathan Drake. And then the curse will be finished."
Jonathan talks with his daughter about his study of the occult and the supernatural. He explains he wanted to learn enough to destroy the curse on the Drake family. Alison does not believe and tells her father so. He decides to show her the Drake family vault. He has the only key and he tells her to keep it. He opens the door and turns on the light in the vault. He explains all Drake family are buried here except Capt. Wilfred Drake, who died in 1873. The curse began with Wilfred. He had a trading station on the upper Amazon. The Jivaro Indians kidnapped his Swiss agent. Wilfred led an expedition into the jungle to rescue the man. They found the agent, but his head was gone. In retaliation, Captain Drake and his men killed every Jivaro man and male child, except one--the Chingui: The Witch Doctor. He escaped and hid in the jungle. The Chinqui placed the curse on the Drake family. Jonathan's father and grandfather were both buried without a head, and both at the age of 60. Jonathan opens a cabinet and shows Alison two skulls. He explains they were returned to the vault by someone or something.
Zutai brings a dutch oven over to Zurich. He pulls a shrunken head out and proclaims, "There it is, finished." It is the tsantsas of Kenneth Drake. He pronounces it, "Perfect." He instructs Zutai to return the skull to the Drake family vault. Rowan arrives at the house. Alison wants to talk to him privately. Zutai watches the pair get into the police car to talk. She tells Rowan that her father thinks he is the next to die. Rowan admits he did routine research on father and daughter. She explains the curse to Rowan while Zutai makes his way into the vault. Rowan asks to see the vault. They enter the vault and look in the cabinet. Now there are three skulls in the cabinet.
Rogers volunteers to bring Jonathan a glass of warm milk to help him sleep. Zutai climbs up a trellis to the professor's bedroom window. He enters, carrying the basket. He pulls a slender stiletto and approaches his victim who sees the creature and recoils. Zutai stabs him lightly on the neck. Next he pulls a bamboo knife from his belt and approaches the paralyzed victim. Before he can remove the head, Rogers enters the bedroom with the milk. Zutai grabs the basket and exits the room via the window.
Rowan and Alison exit the vault. Alison directs the policeman's attention to Zutai climbing down to the ground. Rowan orders the man to hold it. Zutai bolts and Rowan fires at the man. A shot that makes its mark results in a howl like a dog injured. Rowan chases the Indian, but is distracted by a call from Rogers regarding Jonathan Drake. Dr. Bradford attends Professor Drake. He tells Alison, "No sign of a pulse. I'm afraid your father is beyond hope." Rowan notices the small wound on the neck and the blood on the pillow. Rowan asks for the pillowcase to have the blood analyzed.
At the crime lab, Lee Coulter (Frank Gerstle) examines the poison under a microscope. He tells Rowan, "Yeah, its poison all right, curare." Rowan calls Bradford on the telephone. Lee tells Rowan the only people who use curare are South American Indians. Rowan tells Bradford to get Drake an antidote for curare poisoning. Rowan and Lee Coulter enter the Drake vault. Rowan wants prints from the skulls. While Coulter checks for prints, Rowan looks for a way into the vault other than the door. Coulter finds prints on the skulls, but they have at their center a human skull on each fingertip. Rowan asks Lee to check all the other skulls for fingerprints. Lee finds the same weird prints. Rowan wants to talk to Bradford and Alison. Bradford explains that since curare is a phenolic alkaloid, the antidote was easy to find and administer. Jonathan begins to come around. He sees four skulls floating above his bed. His pulse returns to normal. Rowan asks Dr. Bradford if someone could live long enough to have placed all three skulls in the crypt. Alison finds a page in a book that describes the skulls on the fingertips. A chapter describes, "The Cult of the Headless Men was composed of High Priests or Witch Doctors of jungle tribes, deep in the Amazon Jungle." It also states that they were immortal and needed no food or oxygen. Rowan and Alison go for a walk outside. Alison spots a sandal on the ground. Rowan picks up the sandal, but sees no footprints. Then he spots the bullet he fired at the Indian wedged in the bark of a tree. He pries it out and takes both items to the crime lab.
Zurich sits on a throne with a tribal mask covering his face. He chants, "Jonathan Drake, your life was saved by Dr. Bradford. But it will not happen again. And now, you will hear my words. You will hear what I say to you. My words will enter into your mind. You will see what I see." In his bed, Jonathan tosses and turns. "Nothing can save you now, watch as your skull joins the others." Drake knocks over a lamp, which brings Dr. Bradford and Alison into his room. Bradford tells Rogers to get an ambulance, immediately. Bradford gives him an injection. An ambulance arrives, but Bradford takes a taxi to see Zurich at his home rather than attend his patient. Bradford asks Zurich about curare and the Jivaro Indians. Bradford divulges that curare was used on Kenneth and Jonathan. Zurich acknowledges he knew, and tells Bradford he will never leave his house. Zutai dispatches the doctor with the curare tipped stiletto.
At the lab, Lee analyzes the sandal and the bullet. He tells Rowan he hit something with the bullet, but the blood was more curare than blood. The sandal is made from human skin. Rowan proposes to talk to Zurich. He drives over to the Zurich home. He is invited in by the archaeologist. Rowan explains he hit something with a bullet and the lab explained it was stained with blood and curare. Zurich responds, "That is strange. Quite strange, indeed." Zurich suggests the supernatural and that headhunting is still practiced in the world. Rowan notices a blood stain on the rug. Zurich explains the process, telling Rowan the skull could not be damaged, and that the blade must be bamboo, never metal, and then shrinking the skin with hot sand. Before he departs, Rowan tells him about the human skin sandal. Zurich tells Zutai to get things ready, the disposition of Jonathan Drake must be done now.
Rowan calls Coulter on the police radio. He asks Lee to get a rundown on Zurich. Rowan reports he will return to the house to check on a blood stain. Zurich and Zutai drive over to the Drake home. They see a policeman on patrol. Rowan arrives at the Zurich house, breaks in with a skeleton key. Zutai disables the patrolman with a rock upside his head. He climbs the trellis. Rowan enters the house and checks the stain on the rug. He discovers the secret entrance to the basement. Zutai enters the bedroom and finds it empty. Rowan discovers the cauldron boiling and finds the display of shrunken heads. In a cold storage locker he finds the head of Dr. Bradford. Zutai leaves the house with his empty basket. Zurich walks to the Drake home and asks for the Professor. Rogers tells him he is at the hospital. Zurich plans to kidnap Alison. Rowan finishes in the house and calls Coulter from the police car radio. He asks about Zurich. Coulter advises Jeff Rowan to come back to headquarters, and fast.
A taxi brings Alison home. Zurich intercepts her before she can go into the house. He lies and tells her that her father has taken a turn for the worse. He volunteers to take her to the hospital in his car. Coulter tells Rowan about Zurich. There is no Emile Zurich, the person Rowan was with is 180 years old or more. He was the agent for Drake and he was reported killed by the Jivaro Indians on the Amazon River almost 200 years ago. Rowan proposes to return to the Drake house. A taxi pulls up to the Drake house and Jonathan gets out and tells the driver to stay. Rogers reports not seeing Alison to Jonathan. Jonathan tells Rogers that Zurich is holding Alison prisoner. The professor gets a revolver and leaves the house. Zurich proudly shows Alison the whole process for preparing a tsantsas using Dr. Bradford's head. Alison is tied to a chair and horrified when told her father is next. Professor Drake goes to the Zurich house. He enters and looks around. Rogers tells Rowan the story about Alison and Professor Drake. Rowan drives to the Zurich house. Zurich tells Alison, "When your father dies, when the tsantsas made with his head joins the others, then the ancient pledge will be fulfilled and I shall rest." Jonathan enters the basement and confronts Zurich. He concurs that a bullet won't kill a living dead thing, the head of a decapitated white man on the body of a jungle Indian. Drake threatens to blow his brains out with the gun. He knows the skull must be whole, "Once the skull is damaged, the soul will escape and you will have lost." Zutai enters and grabs Drake. They wrestle to the ground. Rowan enters the basement and shoots Zutai who howls like a dog. Rowan and Zutai struggle. Zutai is pushed into the fire and explodes into smoke and fire. Zurich makes a run for it. In the process, Rowan pulls open his surgical tunic and reveals a white man's head stitched onto a brown torso. Drake gives Rowan the curare tipped stiletto and instructs him to break the skin with it. Rowan gives chase and Drake and Alison follow. Drake holds the bamboo knife. Zurich runs to the Drake vault where Rowan waits for him on top. Rowan jumps down on the thing known as Zurich and they struggle. Rowan pricks the man's neck and Zurich falls over and collapses. Drake severs the Zurich head from the Indian body with the bamboo knife. We close with a scene of the decapitated body that turns into dust and the skull sitting nearby on the lawn. Drake says, "The fourth skull."