A group of thieves break into a chamber expecting to find paintings, but instead they release the count himself, who travels to New Orleans to find his nemesis' daughter, Mary Van Helsing.
Matthew Van Helsing (Christopher Plummer), the alleged descendant of the famed 19th century Dutch medical doctor, Abraham Van Helsing, owns an antique shop in early 21st century London. One night with Van Helsing upstairs, his secretary, Solina (Jennifer Esposito), allows a group of thieves, led by her boyfriend, Marcus (Omar Epps), into the shop. The thieves infiltrate the shop's underground high-security vault and find a sealed silver coffin protected by a deadly defense system. Based on the level of security surrounding the coffin, Solina and Marcus decide that the coffin’s contents must be valuable, so they escape with it and flee to New Orleans, Louisiana. When Van Helsing discovers that the coffin has been stolen, he boards a plane to America, telling his apprentice, Simon Sheppard (Jonny Lee Miller), to remain in London. Simon does not follow his mentor’s orders and travels to Louisiana as well.
Aboard the plane, one of the thieves manages to open the coffin, revealing the dormant body of Count Dracula (Butler). Dracula awakens and attacks the thieves, causing the plane to crash in the Louisiana swamps. Dracula survives the crash and travels to New Orleans where college students Mary Heller (Justine Waddell) and Lucy Westerman (Colleen Fitzpatrick) are living. Mary is estranged from her family and has recently been plagued by dreams of a strange, terrifying man.
Van Helsing and Simon arrive in New Orleans and destroy the newly turned vampires left in Dracula’s wake. After the battle, Van Helsing reveals to Simon that he is in fact the original Abraham Van Helsing who defeated Dracula in 1897. Because he was unable to destroy Dracula permanently, Van Helsing hid Dracula's body and prolonged his own life with regular injections of Dracula's blood until, one day, he could discover a way to kill Dracula for good. Simon is intrigued by Dracula's hatred of all things Christian and wonders why Dracula is also particularly vulnerable to silver.
Van Helsing also tells Simon about his daughter, Mary, who was taken from England by her mother after the truth about his identity came to light. Since Mary was conceived after Van Helsing began his injections, she shares blood and a telepathic link with Dracula. Van Helsing knows that Dracula senses Mary's existence and is in New Orleans to find her.
Van Helsing and Simon try to reach Mary before Dracula does, but fail to do so before Dracula turns Lucy into a vampire. Dracula and his three new brides, Solina, Lucy, and Valerie (a news reporter, bitten after the plane crash), corner Van Helsing and kill him. Simon and Mary escape, only to be captured by Dracula shortly thereafter.
Dracula takes Mary to a rooftop and reveals his secret: He is none other than Judas Iscariot, the one who betrayed Jesus for a bribe of thirty pieces of silver. As he went to hang himself, the rope snapped and as punishment he was cursed and had to live for two thousand years as a vampire. The three brides appear with Simon, and Dracula tells Mary to bite him. However, Mary takes the opportunity to save Simon's life by faking the bite instead. Then, together Mary and Simon kill the three brides. Angered by this, Dracula tries to throw her from the rooftop. Mary wraps some cable from a large crucifix around Dracula's neck and they both fall from the roof. Dracula hangs as he attempted to do two thousand years before, but this time the rope does not break, and he burns in the first sunlight. While Dracula dies during the fall, Mary survives the fall. In the end, she is unaware if the sun has truly killed Dracula and vows to watch over his ashes should he ever rise again.