Set against the dark backdrop of Transylvania, in 1887 this fast-paced tale sparks off when Doctor Victor Frankenstein creates a monster with the anticipated aid of Count Dracula, who reveals that he plans to use the creature for his own evil plans and kills the doctor as his castle is raided by a mob of villagers. His assistant Igor escapes, but the villagers chase the monster to an old windmill and set it ablaze. The villagers are scared off by Dracula and his brides, who witness the monster and the doctor's research apparently destroyed by the fire.
One year later, after killing the elusive Mr. Hyde in Paris, monster hunter Van Helsing returns to the Vatican in Rome. He learns his mission to destroy Dracula and his amnesia are penance for past, unremembered sins that cause nightmares. He is tasked with helping the last of bloodline, Velkan Valerious and his sister Anna, who must kill Dracula before their ancestors may enter Heaven. Carl, a friar provides Van Helsing with aid and weapons.
Meanwhile, in Transylvania, Velkan is apparently killed during an attempt to trap and kill a werewolf, and Anna is attacked by Dracula's brides shortly after Van Helsing's arrival. He saves her life and kills Marishka, one of the brides, but as the last of her line Anna becomes more determined to kill Dracula.
That night, she encounters Velkan, who reveals Dracula has a dark secret, but to her horror, he becomes a werewolf and attacks. After she and Van Helsing track him to Frankenstein's castle, they discover that the vampires are attempting to give life to their born-dead children, using Velkan as the source of the power. Van Helsing, dubbed "Gabriel" by Dracula, realizes they had ties in the past. Van Helsing refuses Dracula's offer to return his memory and escapes.
Frankenstein's experiment fails however, and the vampire children die, but Velkan turns on Anna as he becomes completely consumed by his curse. The pair then escape together.
Under the remains of the old windmill, Van Helsing and Anna encounter the monster. Because he is not evil, Van Helsing cannot allow it to be killed, even though he claims to be the key to the failed experiment. The werewolf witnesses this and escapes to inform Dracula.
Meanwhile, Carl discovers a painting that comes to life, depicting a werewolf and a vampire battling. They travel by carriage to Budapest, successfully luring the remaining brides into a trap and killing Verona. Velkan ambushes the real carriage and bites Van Helsing before being shot and killed. Anna is captured and held as a bargaining chip to exchange her for the monster.
They hide the monster in a crypt, but he is taken by the count's undead underlings while Van Helsing and Carl rescue Anna from the count's trap. Returning to the Valerious' castle, Carl discovers an inscription, part of which Van Helsing received in Rome and creates a doorway to the castle.
After failing to free the monster from his imprisonment, he lets them know of a cure to lycanthropy that Dracula possesses. Carl determines that the bite of a werewolf is the only way to kill Dracula. He and Anna take Igor to find the cure while Van Helsing goes to free the monster. Igor escapes while the final bride, Aleera, assaults Anna as Carl tries to deliver the cure to Van Helsing.
After escaping, the monster saves Anna and urges her to help Carl and Van Helsing. She kills Aleera and arrives at the castle. Meanwhile, the werewolf Van Helsing and Dracula battle. Dracula tries to reason with the werewolf, but Van Helsing bites Dracula, who dissolves into a skeleton. Anna bursts in and is attacked and killed by Van Helsing, but not before she delivers the cure. Van Helsing returns to normal, stricken with grief over what he has done.
At a pyre funeral, Van Helsing witnesses the spirits of Anna and her family ascending into the clouds while Frankenstein's monster rows away on a raft out to sea. Van Helsing and Carl ride off into the sunset.