Over the two years since the death of Deacon Frost, Blade (Wesley Snipes), the Daywalker, a vampire unaffected by sunlight and who chooses to defend humans and fight other vampires, has been trying to find his mentor Whistler (Kris Kristofferson), who survived his suicide attempt in the first crisis. Blade has been sweeping across Russia and eastern Europe, enlisting the aid of a young man, Scud (Norman Reedus), to design him a new line of gadgetry and weaponry. Blade carves his way through a large gang of vampires, sparing one, Rush (Santiago Segura), when he promises to reveal Whistler's location. Blade tells Rush he will be back for him. Blade finds Whistler locked in a tank by a gang of vampires who were keeping him alive to torture. Blade rescues Whistler and brings him back to the lair, ridding the latter's vampirism with a cure developed by Dr. Karen Jenson.
A group of vampires look for the hidden resting place of Drake, also known as Dracula—the genetic "father" of their species. They find him in a Syrian ziggurat tomb, although not before, in a moment of blood lust, he kills one of them. The vampires capitalize on Blade's reputation as a serial killer and frame him for the killing of a familiar. During the ensuing manhunt, the FBI locate Blade's latest hideout, and, during the siege, Abraham Whistler dies. With his mentor gone and surrounded by human authorities, Blade allows himself to be captured and arrested.