A year later, monster hunter Van Helsing kills Mr. Hyde after a fight at Notre-Dame de Paris. Van Helsing suffers from amnesia and kills evil in the name of Vatican City, hoping to gain redemption for his forgotten sins. He is charged by Cardinal Jinette with going to Transylvania and destroying Dracula. He must also protect the last members of an ancient Romanian family, the Valérius, whose ancestor swore that his descendants would kill Dracula or fall into Purgatory. He receives a torn parchment on which we can read /"In the name of God, open this door/" in Latin.
Van Helsing travels to Transylvania, accompanied by Carl, an eccentric brother and inventor. Anna and Velkan Valerious attempt to kill a werewolf controlled by Dracula, but he and Velkan fall into a river. Van Helsing and Carl arrive at a village, where they and Anna are attacked by Dracula's three brides – Verona, Marishka and Aleera. Van Helsing kills Marishka. Anna agrees to work with Van Helsing, but meets Velkan, now cursed to become a werewolf during a full moon.
The two follow Velkan to Castle Frankenstein, now used by Dracula to attempt to replicate Dr. Frankenstein's experiments to bring his undead children to life, using Velkan as a conduit. While Anna attempts to save Velkan, who succumbs to his curse, Van Helsing confronts Dracula, who expresses familiarity with Van Helsing, calling him "Gabriel" and offering to restore his memories. Van Helsing and Anna flee the castle, with Dracula discovering that his experiment has failed. Carl witnesses a painting come to life, depicting two knights transforming into vampires and werewolves respectively.
Van Helsing and Anna reach a deep cave beneath the destroyed windmill, where they encounter Frankenstein's monster, who is the true key to realizing Dracula's plans. Van Helsing chooses to shelter the monster in the Vatican. Just outside of Budapest, the group is ambushed by the brides and Velkan. Verona and Velkan are both killed, but not before the latter bites Van Helsing, cursing him to become a werewolf. Anna is kidnapped by Aleera, who arranges with Van Helsing to exchange her for the monster. Van Helsing locks the monster in a crypt, but he is captured by Dracula's undead horde. Van Helsing and Carl save Anna by using a solar bomb created by Carl to destroy the vampires.
Back at the Valerious family castle, Carl explains that Dracula is actually the son of Anna's ancestor, imprisoned in an ice fortress, hidden behind a large fortified map of Transylvania. Using the torn parchment, Van Helsing opens the gate and finds Dracula's fortress. The captured monster informs Van Helsing that Dracula has a cure for lycanthropy; Carl realizes that only a werewolf can kill Dracula. Capturing Igor, Van Helsing sends him, Anna and Carl to retrieve the cure, while he frees the monster. As he does so, the monster is struck by light twice, bringing Dracula's children to life. Dracula, spotting Van Helsing, transforms into a demonic form, fighting Van Helsing in werewolf form. Aleera and Igor are both killed while Anna and Carl retrieve the cure. Following a violent skirmish, Dracula then reveals to Van Helsing that he is in fact the archangel Gabriel and that it was he who murdered Dracula. Dracula offers to restore all of Van Helsing's memories, but he refuses, stating that some things are better forgotten. Van Helsing then bites Dracula's throat, killing him and his children. Van Helsing then kills Anna, but not before she delivers the cure.
Van Helsing and Carl hold a funeral for Anna overlooking the sea, from which the monster leaves by boat. Van Helsing witnesses Anna's spirit reuniting with her family in heaven, freed from their vow. Van Helsing and Carl set off on their next adventure.
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