十九世纪，罗马尼亚存在着一个人鬼共存的神秘地带――特兰西尼亚古镇。镇上有一支邪恶势力在天黑后统治着该地区，那就是吸血鬼德古拉（理查德•劳斯伯格 Richard Roxburgh 饰）领导下妖魔鬼怪。他们一到日黑就出来大肆杀戮，手段异常残忍。更加恐怖的是，这个队伍在不断壮大中，噬血的科学怪人也不远万里投靠了德古拉。 罗马尼亚的天主教在多次征剿失利后，远赴美国请来了吸血鬼猎人范海辛（休•杰克曼 Hugh Jackman 饰）。范海辛带着助手前往特兰西尼亚途中，巧合下救了另一位吸血鬼女猎人――安娜（凯特•贝金赛尔 Kate Beckinsale 饰）。安娜因为家族世代受到德古拉的诅咒而家破人亡，从小练就了一套猎鬼本领。安娜和范海辛一拍即合，共同前往对付德古拉……
Gabriel Van Helsing (Hugh Jackman) has been ordered by the Vatican to search out and destroy Count Vladislaus Dracula (Richard Roxburgh), an assignment that doesn't make Van Helsing very happy. He is tired of killing monsters for the Church, only to be branded by the public as a murderer with a price on his head. He also wishes that he had back his memories, something that was taken away from him due to his previous sins. Cardinal Jinette (Alun Armstrong) explains that this assignment is important because, 450 years ago, a Transylvanian knight named Valerius the Elder promised God that his family would never rest nor enter heaven until they vanquished Dracula. However, Dracula still lives, but only two of Valerius' descendents -- Princess Anna (Kate Beckinsale) and Prince Velkan (Will Kemp) -- remain. The Valerius family is running out of time, and the Church is committed to saving their souls. So, armed with only a scrap of a picture, rings of garlic, holy water, a silver stake, a crucifix, an automatic crossbow, and Friar Carl (David Wenham), the Q of the Vatican, Van Helsing takes off for Transylvania.
Van Helsing's arrival in Transylvania is not well met, as Transylvanians don't like strangers. As Princess Anna challenges their business there, Van Helsing notices three harpies flying towards them. They are Dracula's three brides -- Aleera (Elena Anaya), Marishka (Josie Maran), and Verona (Silvia Colloca). It's obvious that they are trying to nab Anna. In fact, they succeed in carrying her off several times, but Van Helsing manages to get her back. He finally destroys Marishka by dipping his crossbow in holy water before shooting her with a dart. Oddly, the villagers are angry with Van Helsing for killing Marishka. They explain that the vampires only kill one or two a month to satisfy their needs. Now, thanks to him, they will kill more out of revenge.
Dracula isn't happy about it either. Not only is he now short one bride, but a year ago, after setting up Victor Frankenstein (Samuel West) with his own laboratory, the villagers set Frankenstein's monster on fire, and Dracula needed the Monster in order to give life to his offspring (Dracula's children are born dead and must be animated). Then, just a few days ago, Velkan Valerius destroyed Dracula's werewolf with a silver bullet, although it cost Velkan his life when the werewolf grabbed him just before he fell over a steep cliff.
Grateful that Van Helsing saved her life and destroyed Marishka, Anna takes Van Helsing and Carl back to the castle where the Valerius family has lived for hundreds of years following Dracula's human death. That evening, Anna wants to go out vampire hunting, but Van Helsing, preferring to wait until daylight, sprays her with knockout spray. When Anna later awakens, the halls are dark and Van Helsing is nowhere to be found. Still, someone is there. It's a werewolf, but not just any werewolf. It's her brother, Velkan. Apparently, Velkan was bitten by the werewolf on the way down, survived the fall, and now he is a werewolf, too. When the moon suddenly goes behind a cloud, Velkan changes from werewolf back to himself just long enough to warn Anna. Then the moon comes out, and he changes back into a werewolf and lunges at her. Van Helsing appears and fires a shot at Velkan, but he leaps out the window. Van Helsing follows. Just when Van Helsing gets a clear shot at Velkan, Anna stops him to let him know that Dracula supposedly has a cure for werewolfism. Van Helsing agrees to help Anna look for the antidote and try to save her brother.
