The people of the village of Frankenstein are under a curse and blame it on the Doctor’s Monster. They attack and destroy Castle Frankenstein and the monster ((Lon Chaney Jr.) is released from its tomb by the explosions. Ygor (Bela Lugosi) and the monster flee the castle and the latter is struck by lightning. Ygor intends to find Ludwig Frankenstein (Sir Cedric Hardwicke), second son of Henry, and force him to help the monster regain its strength.

With his assistants, Doctor Kettering (Barton Yarbrough) and Doctor Bohmer (Lionel Atwill), Ludwig has a practice in Visaria, and Ygor and the monster go there. The monster befriends a little girl, Cloestine Hussman (Janet Ann Gallow). He carries her up to a rooftop to retrieve her ball and unfortunately kills two villagers who intervene. When the monster returns the girl to her father, Herr Hussman (Olaf Hytten), he is seized by police. The town prosecutor, Erik Ernst (Ralph Bellamy), requests that Doctor Frankenstein examine the giant. Ygor begs him to heal the monster, but Ludwig refuses until Ygor threatens to out him as a monster-maker.

At the police station, the creature is in chains and when Ludwig denies recognizing him, he breaks free in a fit of rage. Elsa (Evelyn Ankers), Ludwig’s daughter, finds and reads the Frankenstein journals. After killing Doctor Kettner, the monster grabs Elsa, but is subdued with knockout gas. Ludwig tranquilizes the monster and asks Doctor Bohmer’s help in dissecting the creature. But Bohmer refuses as that would be murder. The ghost of Henry Frankenstein appears and asks Ludwig to supply the monster with a good brain. Ygor offers his, but Ludwig refuses because the thought of Ygor’s twisted brain in an indestructible body is horrifying. Elsa begs Ludwig to stop altogether, but he refuses that too. Ygor tempts Bohmer to rebel against Ludwig by using Ygor’s brain.

The police and Erik arrive to search the chateau and find the secret room, but Ygor and the monster are gone. Ludwig performs the operation, not knowing that Bohmer has replaced Kettering’s brain with Ygor’s. When the monster rises, Ludwig is shocked to hear Ygor’s voice. The villagers storm the chateau and Ygor tries to gas them and mortally wounds Ludwig, but the mix of Ygor’s and the monster’s different blood-types makes the Ygor-monster go blind. He kills Bohmer, setting fire to the chateau and dying in the conflagration. Erik and Elsa escape.

The film was directed by Erle C. Kenton. It was the first in a series with Lon Chaney as the monster. Boris Karloff could not play the role because he was filming Arsenic and Old Lace. Chaney was allergic to the makeup and missed several days of shooting. At one point, the company went to lunch and left Chaney under hardening fake concrete, breathing through a tube. His mask was so uncomfortable that he ripped it off his face, injuring himself. He would often arrive with ice cream for all the children. When Janet Ann Garrow’s mother died, he wanted to adopt the girl, but her father said no. After putting on the makeup and costume, Chaney, already a big man, was 6-foot-9 and 284 pounds.

Reviews were mixed. Some said that the film seemed cobbled together from bits and pieces, rather like the monster, actually, but it was full of action and peril. The score by Hans. J. Salter received honors. Sir Cedric Hardwicke played the Ghost of his father even though his mellow baritone was nothing like Colin Clive’s clipped, nervous speech, but Clive was dead. The ghost in the title appears on screen for less than two minutes. Several characters appear even though they had died in the previous film, with no explanation. This was the only film in the series in which a Frankenstein dies on screen, and it was the final appearance of Frankenstein’s monster in the series without sharing billing with another monster.