The residents of Frankenstein's village feel they are under a curse and blame the monster Lon Chaney Jr. for their troubles. The Mayor allows the townspeople to destroy Frankenstein's castle, hoping to end the fear that shadows them. Ygor locates the monster after its sulfuric tomb is breached by explosions; the sulfur exposure has weakened the creature while somehow preserving it. A bolt of lightning strikes the fleeing monster, and Ygor resolves to have Ludwig Frankenstein [Cedric Hardwicke], the doctor who now practices in Visaria, help restore the creature’s strength. Ludwig is the son of Henry Frankenstein, and his work becomes entangled with a troubling past.
Ygor and the monster arrive in Visaria, where the creature befriends a young girl, Cloestine Hussman [Janet Ann Gallow]. The monster carries Cloestine up to a roof to retrieve her ball, and in the process tragedy strikes as two villagers are killed by accident. When Cloestine asks to be brought down, the monster complies, but is subsequently captured by the townspeople. The town prosecutor Erik Ernst [Ralph Bellamy] arrives later and asks Ludwig to examine the captive giant. Before that can happen, Ygor visits Ludwig and reveals that the giant is the monster. He pleads with Ludwig to repair the monster’s body and brain, but Ludwig refuses, and Ygor retaliates by blackmailing him with the threat of exposing Ludwig’s family history to the villagers.
At the courthouse, the monster is restrained as a hearing examines the recent murders. Ludwig denies recognizing the creature, and the monster breaks free in a furious outburst, only to be led away again by Ygor. Elsa Frankenstein [Evelyn Ankers], Ludwig’s daughter, discovers the Frankenstein journals and pieces together the family history. She spots Ygor and the monster in a window and, after breaking into Ludwig’s laboratory, witnesses the monster kill Dr. Kettering [Barton Yarborough]. The monster grabs Elsa, but Ludwig subdues him with knockout gas, setting off a chain of events that advances his manipulative experiments. As the monster lies unconscious, Ludwig begins to study him, contemplating dissection with Bohmer’s reluctant help.
Ludwig is visited by the ghost of his father, Henry Frankenstein, who urges him to end the monster’s torment by giving him a good brain. In a tense moment, Ludwig tells Bohmer and Ygor that he plans to transplant the brain of the late Dr. Kettering into the monster. Ygor protests that he will lose his friend and offers his own brain for the operation, but Ludwig remains wary and distrustful of Ygor’s nature. Elsa pleads with Ludwig to abandon the dangerous experiments, but he remains determined. Ygor, meanwhile, pressures Bohmer to assert his independence from Ludwig’s authority, promising to help if Ygor’s brain can inhabit the monster.
Police descend on Ludwig’s house in search of the monster, but Ygor and the creature have escaped. The monster abducts Cloestine again and returns to Ludwig’s chateau, insisting that Cloestine’s brain be placed inside his own head. Cloestine does not want to lose her brain, and the monster reluctantly returns her to Elsa. Ludwig proceeds with the surgery, unaware that Bohmer has removed Ygor’s brain instead of Kettering’s, a crucial and catastrophic mistake.
Herr Hussman stirs up the neighbors, claiming his daughter has been captured by the monster and that Ludwig is hiding it. Ludwig reveals the “moral brain” plan to Erik Ernst, claiming that the monster has been redeemed, but the creature declares that he is not Kettering—he is Ygor. The villagers storm the chateau, and the Ygor-monster uses Bohmer to fill the house with gas in a bid to wipe them out. Ludwig tries to intervene, but the Ygor-monster overpowers him, mortally wounding Ludwig. The brain-mismatch leaves the Ygor-monster blind, a grim consequence of the failed procedure. In a fit of fury, he hurls Bohmer onto the apparatus, electrocuting him, and accidentally starts a fire that consumes the chateau. Trapped by the flames, the Ygor-monster is left behind as Erik Ernst and Elsa Frankenstein escape, stepping out into the first light of dawn.
