Grave robbers open the coffin of Lawrence Talbot (Lon Chaney, Jr) five years after his death, only to have the full moon bring him back to life.
Transforming into the Wolf Man, Talbot attacks the grave robbers and wakes up under the care of Dr. Mannering (Patric Knowles) in a hospital in Cardiff, miles from his hometown. He escapes and seeks out the gypsy woman Maleva (Maria Ouspenskaya) who first told him about the curse when he was bitten. She promises to help him and does so by travelling with him to Vasaria to seek the assistance of Dr. Ludwig Frankenstein.
Due to the events of The Ghost of Frankenstein, the doctor is dead and his house burned to the ground by the time they arrive.
Talbot searches the ruins of the Frankenstein estate and finds Frankenstein's monster, weakened by the events of The Ghost of Frankenstein, but no records. He then finds out that Frankenstein's daughter Elsa (Ilona Massey) is still alive, and contracts to buy her property as an excuse to meet her and ask for her assistance.
In the meantime, Mannering has been chasing Talbot down and finds him in Vasaria. The monster appears in the village, sending panic through the residents until Talbot escapes with him into the countryside. Elsa promises the town she will help Mannering find and destroy the monster, and leads Mannering to the ruins where they find Talbot and the monster.
Mannering is sympathetic towards Talbot's plight and agrees to help him if he can find Frankenstein's records, which Elsa provides. Mannering quickly becomes distracted from his promise to help Talbot and re-energizes the monster.
The villagers, knowing none of these events, become impatient waiting for news and one brash saloonkeeper decides to blow up the dam upstream of the Frankenstein estate.
Once the monster is re-energized, he attempts to carry Elsa off but the Wolf Man comes to her rescue. Elsa and Mannering flee the castle as the monster and the Wolf Man fight, then the dam blows up and the estate is completely flooded, killing both the monster and the Wolf Man.