The film focuses on a small group of overzealous scientists who hope to use Dracula's desiccated - but still alive - body to discover the secret of immortality. Elizabeth Blaine, working at the New Orleans morgue, receives Dracula's 'corpse' from her friend and co-worker Luke following the events of Dracula 2000. (This is a departure from the epilogue of the first film, in which Mary Van Helsing explains in a voiceover that she had returned Dracula to London and assumed her father's duties as Dracula's keeper).
Elizabeth examines the body and pricks her finger on a fang in what is supposed to be a human mouth. This leads her to alert her boyfriend Lowell, who is suffering from an ultimately fatal degenerative sickness. Lowell claims a wealthy investor wants to fund their research into the mysterious corpse (assuming the explanation for its condition is natural rather than having anything to do with the supernatural). They spirit the body away.
On their heels is Father Uffizi, seemingly the Vatican's official vampire hunter. He has been given the task of not only killing Dracula, but granting him absolution (the Church realizes that Dracula is in fact Judas Iscariot). This will allow the vampire to rest in peace. What the Cardinal giving Uffizi this task may or may not know is that the priest was scratched by a vampire fang in a previous hunt. Each day he exposes himself to the sun, burning out the vampiric infection while he screams in pain.
Luke (who secretly loves Elizabeth) doubts that Dracula is a purely natural phenomenon. He surrounds the now-awake (but severely weakened) vampire with folkloric wards like mustard seeds and knots. Elizabeth, meanwhile, feels increasingly strange as the infection in her grows, as does her attraction/bond to Dracula.
Finally, another member of the team injects himself with Dracula's blood, becomes a vampire and goes out to feed. He kills a woman, making her undead like himself. Uffizi finds and kills them both, then backtracks.
The truth comes out about Lowell. There is no "secret investor". Seeking a cure for his illness, Lowell has used Elizabeth and the others ruthlessly. An injection "cures" him but he survives mere moments before Uffizi arrives. Uffizi tells Elizabeth, now on the verge of becoming a vampire herself, to enter the sunlight. He says it will be agony, but the vampiric part of her will be burned away. Before that the now faceless Eric (dracula tore off Eric's face) attacks Uffizi and the others, Luke grabs a bottle of holy water and then jams the holy water in Eric's throat. Eric chokes on the holy water then dies. Then Uffizi goes after a now-free Dracula after noting that Luke will make a great vampire hunter someday.
Uffizi catches up with Dracula and during the showdown, Dracula taunts him with the fact Elizabeth will simply die and Uffizi knows it.
- Jason Scott Lee as Father Uffizi
- Jason London as Luke
- Khary Payton as Kenny
- Craig Sheffer as Lowell
- Diane Neal as Elizabeth Blaine
- Brande Roderick as Tanya
- Tom Kane as the voice of Cartoon Voice of Doctor
- John Light as Eric
- Stephen Billington as Dracula/Judas Iscariot
- Nick Phillips as Officer Smith
- John Sharian as Officer Hodge
- Roy Scheider as Cardinal Siqueros
- David J. Francis as Jesus