In the year 1891, a desperate Gwen Conliffe (Emily Blunt) reaches out to Lawrence Talbot (Benicio Del Toro), informing him that his brother, Ben, has gone missing. Lawrence, well-known as a Shakespearean actor, abandons his London tour to return to the dilapidated Talbot Hall in Blackmoor, where he has been estranged from his family since his father, Sir John Talbot (Anthony Hopkins), confined him to an asylum after the tragic passing of his mother.
Upon arrival, he learns from John that Ben's mutilated remains were discovered just the day before. Lawrence ventures into town to view the body, located at the local slaughterhouse, where he receives Ben's personal belongings. While at a local tavern, he overhears townsfolk discussing the horrifying event; many suspect a group of gypsies camped outside the town, while a man recounts a historical case where a similar murder occurred, which John's father believed to be the work of a werewolf. Among Ben's possessions is a medallion associated with the gypsies.
After Gwen leaves for London, Lawrence infiltrates the gypsy camp on the night of a full moon. Maleva (Geraldine Chaplin) warns him of the malevolent force that has claimed his brother. Chaos erupts as townspeople confront the camp, seeking a dancing bear they believe is the killer, only to be attacked by an overpowering wolf-like creature. In a bid to save a young boy fleeing into the woods, Lawrence is viciously attacked by the beast, which bites him before vanishing under the onslaught of armed locals. Maleva attends to his wounds but warns that he may no longer be entirely human, as only a loved one can end what he has become.
Gwen returns to nurse him back to health, and after several harrowing dreams, he seems to recover. John's devoted servant, Singh (Art Malik), reveals a stash of silver bullets, ominously suggesting a powerful beast lurks in the shadows of Blackmoor. Investigation unfolds as Inspector Abberline (Hugo Weaving) arrives from London, suspecting Lawrence due to his past. Fearing the repercussions, Lawrence sends Gwen away once more.
In a dark twist, Lawrence follows John into the hidden catacombs beneath Lady Talbot's crypt, where he discovers that John, presumed dead for years, has succumbed to a family curse—lycanthropy—after being bitten by a feral boy in India. Lawrence recalls witnessing his father commit a brutal act years ago. Now liberated from restraint, John intends to unleash his monstrous heritage upon the world.
After a shocking transformation during a presentation to medical colleagues, where Lawrence morphs into the Wolf Man beneath the full moon, chaos ensues as he escapes, wreaking havoc across the town. When Lawrence unexpectedly reconnects with Gwen in her antique shop, they affirm their deep love, but danger looms as Abberline arrives searching for him.
As tensions escalate, Gwen researches lycanthropy, seeking Maleva's guidance. Tragically, Maleva confirms Lawrence's fate as irreversible, and Abberline empowers himself with silver bullets for their confrontation. Upon returning to Talbot Hall, Lawrence discovers Singh's horrific demise and gears up for a fight against John. They both succumb to their werewolf forms during a fierce battle, igniting the very room in which they confront each other.
In a devastating climax, Lawrence manages to push John into the fire, ultimately confronting Gwen with the terrifying side of his dual existence. As Abberline arrives to confront Lawrence, a heart-wrenching resistance stirs within him, but ultimately, Gwen, caught in a moment of desperation, retrieves a gun and executes the agonizing duty of ending his torment, unleashing Lawrence's humanity one last time as he succumbs to his injuries.
As fires blaze through Talbot Hall, an ominous howl echoes, hinting that Abberline, too, has fallen victim to the curse of the wolf.
