In 1760, the Collins family migrates to America from Liverpool and sets up a fishing port in Maine, naming it Collinsport. Some years later, the son, Barnabas (Johnny Depp), seduces his family's maid, Angelique Bouchard (Eva Green), who is a witch. When he tells her he doesn't love or want her, Angelique kills Barnabas' parents. Barnabas then falls in love with Josette du Pres (Bella Heathcote). In a fit of jealousy, Angelique bewitches Josette into leaping from a cliff to her death. Barnabas leaps after her in grief, but he survives because Angelique turns him into an immortal vampire. She rouses a mob to capture and bury Barnabas alive in a chained coffin in the woods and curses his family.
One hundred ninety-six years later, in the year 1972, construction workers accidentally free Barnabas from his coffin, who slakes his two-century hunger by feeding on and killing his rescuers. He makes his way back to his manor to find it inhabited by his dysfunctional descendants and their servants—the family matriarch Elizabeth Collins Stoddard (Michelle Pfeiffer); her brother Roger (Jonny Lee Miller); her 15-year-old daughter Carolyn (Chloë Grace Moretz); Roger's 10-year-old son David (Gulliver McGrath); Dr. Julia Hoffman (Helena Bonham Carter), David's psychiatrist; Willie Loomis (Jackie Earle Haley), the manor's caretaker; and Victoria Winters (Heathcote), David's newly-hired governess and Josette's reincarnation. Upon convincing Elizabeth of his identity by revealing a secret treasure room behind the fireplace, Barnabas is allowed to stay under the condition that he never reveal either the room or the fact that he is a vampire to the rest of the family. He must also pretend to be a distant relative from England who has come to restore the family's business and reputation in town. He soon becomes very deeply attracted to Victoria, whom he briefly mistakes for his lost Josette, and immediately begins to pursue her.
As Barnabas helps revitalize the Collins' fishery and manor, he is approached by Angelique, who has used her powers to establish a successful rival fishery called Angel Bay and live through the decades by posing as her decendants. She tries to win him back, later convincing him to make wild, passionate love with her, but he still rejects her, telling her that he loves Victoria instead. He restores his family's name by inviting the entire town to a party at the manor featuring Alice Cooper, where Victoria reveals to Barnabas that her parents committed her to an insane asylum as a child because she could see and talk to Josette's ghost. They kiss and confess their feelings to each other, unknowingly enraging Angelique who has witnessed the scene. Meanwhile, Dr. Hoffman has discovered Barnabas' true nature after hypnotizing him. She convinces him to try to turn himself back to a regular human via blood transfusions, but her real intent is to use his blood to turn herself into a vampire to avoid aging. Upon discovering this betrayal, Barnabas drains her to death and dumps her body into the ocean. Barnabas catches Roger trying to find the secret room and exposes Roger's lack of interest in his son. Barnabas then gives him a choice of either staying and being a good father to David or leaving the family with suffient funding to satisfy his greed. Roger chooses to leave, deeply wounding his son's feelings. Soon afterward, Barnabas rescues David from a falling disco ball and stumbles into a beam of sunlight, burning his skin and exposing his secret to the horrified children and Victoria.
Later that night, Angelique calls Barnabas into her office, coaxes him into confessing Dr. Hoffman's murder, and traps him in another coffin that she leaves in his family's crypt. She then burns down the Collins' canning factory and plays a recording of the murder confession to the police and gathered townsfolk, once more turning them against the family. Angelique leads the mob to Collinwood manor to arrest the family, but Barnabas is rescued from the coffin by David and he shows up at the manor and attacks Angelique in front of the mob, thereby exposing both his and her true natures. As the townspeople disperse, Angelique sets fire to the manor and admits her role in the family's curse, including turning Carolyn into a werewolf and killing David's mother at sea. Barnabas and the Collins family fight Angelique until David summons his mother's vengeful ghost. The ghost gives a single scream which knocks Angelique into a chandelier. Before she dies she pulls out her heart and offers it to Barnabas; he refuses the heart, trying to make her admit she didn't really love she just wanted to torture him, and it shatters as Angelique dies. Barnabas then discovers that Angelique has bewitched Victoria into jumping off the same cliff Josette did. Barnabas arrives moments before Victoria is about to jump and breaks her hypnosis, but she reveals she wanted to fall. She pleads with him to make her a vampire so that they can remain together forever, but he refuses. She then casts herself off, forcing him to follow and bite her to save her life, and Victoria wakes up as a vampire. As the two kiss on the rocks in the waves, the film ends with an underwater scene showing a school of fish swimming away from Hoffman, who suddenly revives because she managed to transfuse enough of Barnabas's blood into herself.