Deep in a remote desert, vampire leaders are resurrecting Dracula, the horrific creature who spawned their race. Now known as Drake (Dominic Purcell), this awesome vampire has unique powers that allow him to exist in daylight.
The vampiric leadership launches a smear campaign against the vampire hunter Blade (Wesley Snipes), targeting him as a murderous monster and sending the FBI after him. After Blade and his mentor, Whistler (Kris Kristofferson), have an explosive showdown with FBI agent Cumberland (James Remar) and his men, it's evident that the Daywalker will need some assistance. Blade reluctantly teams up with the Nightstalkers, a group of vampire hunters led by Whistler's beautiful daughter, Abigail (Jessica Biel), and the wisecracking Hannibal King (Ryan Reynolds).
While their blind scientist Sommerfield (Natasha Lyonne) works on creating a final solution for the vampire problem, the Nightstalkers launch a relentless series of battles against Dracula's gang of the undead, led by the powerful vampire Danica Talos (Parker Posey) and her fanged acolytes Asher (Callum Keith Rennie) and Grimwood (Triple H). Ultimately, Blade finds himself taking on the greatest vampire of all time, as his own fate and that of humanity hang in the balance.