A cohort of vampires embarks on a mission to locate the concealed resting place of Drake, portrayed by Dominic Purcell, who is also known as Dracula and is regarded as the genetic "father" of their kind. They eventually discover him within an Iraqi Ziggurat tomb, but not before a moment of bloodlust leads him to kill one of their own. Capitalizing on Blade's (played by Wesley Snipes) notorious reputation as a vampire killer, they deceitfully frame him for the murder of a human by making it appear he was responsible as a vampire. Amid the ensuing manhunt, the FBI tracks down Blade's latest hideout, resulting in a siege where Abraham Whistler (portrayed by Kris Kristofferson) meets his demise, sacrificing himself to protect vital research and data. Alone and beset by human authorities, Blade opts to surrender and is taken into custody.
Following futile medical and interrogation attempts, the police prepare to transfer Blade to a group of medics who are, unbeknownst to them, actually vampires. Among them are Danica Talos, the vampire responsible for awakening Drake, her brother Asher, and Jake Grimwood, the vampire enforcer. Fortunately, Blade is rescued by Hannibal King (Ryan Reynolds) and Abigail Whistler (Jessica Biel), Abraham's daughter, both of whom are members of a vampire-hunting faction called the Nightstalkers. They inform Blade that Danica Talos, who once converted King into a vampire temporarily, has tracked down Drake. Given Drake's unique status as the progenitor of vampires, he is impervious to sunlight, and Talos hopes to use his power to eliminate Blade and transform the rest of the vampire populace into Daywalkers.
The Nightstalkers face a formidable challenge as they believe that the number of vampires is too overwhelming to combat individually. With their current strategy killing merely a few hundred each year, Sommerfield, their dedicated chemical specialist, has devised an experimental bioweapon named Daystar, an airborne virus designed to eliminate every vampire on a molecular level.
In their initial confrontation, Drake tests Blade by isolating him from King and Abigail, incapacitating King amidst the tumult. While Drake proves to be physically superior, he shares a strange bond with Blade, as both choose to be "honorable warriors" amid their kind. During a conversation, Drake wields a baby he has taken hostage as leverage, demonstrating his disdain for humanity. Meanwhile, Blade and Abigail uncover a horrific plan by the vampires for a "final solution," involving the use of blood farms where humans are kept in a vegetative state to extract blood. In a heroic act, Blade puts an end to the life support of the victims.
Upon returning, they find that all the Nightstalkers have been slaughtered, except for King and Sommerfield’s young daughter, Zoe. Using these survivors as bait, Drake lures Blade into a confrontation. After watching a posthumous message from Sommerfield, Blade discovers she has completed a small batch of Daystar, which requires Drake's blood to unleash its potential, albeit at the risk of potentially killing Blade himself. Meanwhile, King is tortured for information by Jarko Grimwood and Asher Talos, with Danica subsequently tormenting King through cruel methods.
Blade and Abigail arrive in time, leading to a fierce battle against Talos' minions and the building’s security. After successfully rescuing King and Zoe, a series of confrontations ensue where Abigail manages to take out Asher, while King dispatches Jarko. The ultimate showdown features Blade going toe-to-toe with Drake, culminating in Blade piercing Drake with Abigail's Daystar arrow, releasing the virus and annihilating the surrounding vampires, including Danica. As Drake succumbs, he acknowledges Blade's honorable conduct and warns him that the "Thirst always wins" eventually.
The story unveils multiple potential endings:
- Theatrical Ending: A nod to Blade's honorable fight results in Drake granting him a "parting gift," morphing his dying figure into a likeness of Blade. The FBI mistakenly retrieves this body, believing it to be Blade, which leads them to call off their manhunt. However, during an autopsy, Blade’s body inexplicably transforms back into Drake's form. Hannibal closes with a voiceover, confirming that Blade remains alive, continuing his battle against vampires.
- Unrated Ending: The FBI still retrieves Blade's body, but he is very much alive. As he jolts awake in the morgue, he attacks the agents, leaving the audience questioning whether he retains his humanity or has succumbed to the vampire desires foreseen by Drake.
- Werewolf Ending: The Daystar virus spreads globally, terminating all vampires, while Blade strides into the sunset, reflecting on the conclusion of his long-standing struggles. The final scene shifts focus to the Nightstalkers confronting a new menace: werewolves.
