Barnabus Collins (Johnny Depp) is cursed to be a vampire by Angelique Bouchard (Eva Green) because she was jealous of Barnabus' love for Josette (who Angelique curses to commit suicide by jumping off a cliff). Barnabus is buried alive by Angelique in 1772 and is accidentally freed in 1972 by a construction crew (whom he eats). He returns to his home Collinwood Manor in Collinsport, Maine where his family once we the richest people in town owning a huge fishery, but now his family manor and business is run down and he only has a couple of remaining family members. Elizabeth Collins Stoddard (Michelle Pfeiffer), her daughter Carolyn, her brother Roger and his son David. David is disturbed over the death of his mother and has a live in shrink, Dr. Hoffman (Helena Bonham Carter), and the family has a loyal groundskeeper, Willie Loomis (Jackie Earle Haley), who becomes Barnabus' loyal servant, thanks to the power of hypnosis by Barnabus. Angelique has run the town for two hundred years opening her own fishery which had put the Collins in the poor house, and she is now the richest and most loved person in town (of course nobody knows she's a witch).
Barnabus returns to Collinwood Manor and immediately attempts to restore the family name and business. He falls in love with David's new nanny Victoria Winters who seems to be a reincarnation of his true love Josette. He also falls in love with his new family, with the exception of David's father Roger, who doesn't care about anything but money. Barnabus gives him a choice to stay and be a great father to David or take enough money to be wealthy forever and leave but never look back, he takes the money leaving his heartbroken son without saying goodbye. Dr. Hoffman discovers Barnabus is a vampire, and while pretending to find him a cure, she infuses herself with Barnabus' blood hoping to become a vampire and live forever. When Barnabus discovers her plans he drains her blood, he and Loomis bind her in chains and send her to the bottom of the ocean.
Angelique, still obsessed with Barnabus, makes every effort to destroy the progress the Collins family is making, burning down the fishery, and rallying the townspeople to go after the Collins Family by playing a recording of Barnabus confessing to killing Dr. Hoffman. The rioting town shows up at Collinwood Manor like a lynch mob looking for Barnabus. Barnabus exposes Angelique as a witch to the entire town. A struggle ensues. Carolyn is shown to be a werewolf, and she attacks Angelique. The ghost of David's mother also appears, attacking Angelique and proving that David wasn't crazy after all. As Angelique is dying she professes her love to Barnabus, ripping out her heart and handing it to him. He replies that she is not capable of love, and she dies. Collinwood Manor is destroyed, and Victoria Winters throws herself off the same cliff as Josette. Knowing that the only way for her to be with Barnabus is to also be a vampire, Barnabus jumps after her, biting her as they fall, and as they hit the rocks below she turns into a vampire.
In the very end, Dr. Hoffman wakes up at the bottom of the ocean, also a vampire.