NOTE: Sequel to Blade II (2002).
Prologue: Four fully-covered vampires walk into a stone ziggurat in the Syrian Desert of Iraq. They are looking to re-awaken Dracula. They find him. Only three vampires walk out.
Six months later. Blade (Wesley Snipes) has slipped up. After killing 1,182 human familiars and countless vampires, he's killed an innocent human. Shot him through the heart with a silver stake, but he didn't ash. What gives? It was a set up, staged just to get Blade caught and out of the vampire hunting business.
FBI agents Ray Cumberland (James Remar) and Wilson Hale (Michael Anthony Rawlins) have positively identified Blade, thanks to a video by an anonymous citizen. That "anonymous citizen" is actually Danica Talos (Parker Posey), one of the four vampires who freed Dracula (Dominic Purcell), or "Drake" as he now calls himself.
The FBI has cornered Blade and Whistler (Kris Kristofferson) in their warehouse laboratory, but Whistler is not about to let their operation fall into the hands of the FBI (aware that the FBI is loaded with human familiars as well as a vampire agent or two. After yelling at Blade to get out of the building, Whistler blows it up, destroying everything--computers, weaponry, and himself. Blade is devastated by Whistler's death and he is easily captured. Blade is taken to the police department where he is being poked and prodded by the FBI, who consider him public enemy number one, and by forensic psychiatrist, Doctor Edgar Vance (John Michael Higgins), who has pronounced Blade psychotic and wants to transfer him to County Psychiatric. Police chief Martin Vreede (Mark Berry) pulls jurisdiction and refuses to release Blade to either of them.
While they argue over who should have custody of Blade, Vance shoots him full of tranquilizers. Even in his weakened state, Blade has already figured out that Vance is working for the vampires. Then, Danica Talos and several other vampires, including her brother Asher (Callum Keith Rennie) and strongman Jarko Grimwood (Paul Levesque), posing as a transfer team, arrive to move Blade, but Danica can't hide her vampirism from Blade. Unfortunately, Blade is too knocked out to resist. "You're all alone, Blade", Danica taunts. "No one's going to help you now."
But Danica is wrong. There are some new vampire hunters in town, among them none other than Whistler's illegitimate daughter Abigail (Jessica Biel) and the wise-cracking ex-vampire Hannibal King (Ryan Reynolds), Danica's ex-pet. They come to Blade's rescue, overpowering Danica and her henchmen while Blade doses himself with serum through a new effervescent inhaler (no needles needed).
When Blade's strength has returned, he, King, and Abby break out of the police station, taking out a bunch of vampires along the way. But they're not clear yet. As they exit the building, a dozen police cars drive up, surrounding them. Suddenly, an old van speeds up. King and Abby jump in, with Blade right behind them, and the van speeds away. They drive to Abby and King's "Honeycomb Hideout" where Blade meets the rest of the Nightstalkers, as they refer to themselves. Besides King and Abby, there is van driver Dex (Ron Selmour), weaponry designer Hedges (Patton Oswalt), blind scientist Sommerfield (Natasha Lyonne), and Sommerfield's young daughter Zoe (Haili Page). Although he is informed that it was Sommerfield who fashioned his new serum inhaler and that Whistler wanted Blade to work with the Nightstalkers, Blade is not impressed by them. In his eyes, they are kids...rookies, not to mention that Abby Whistler fights with her MP3 earplugs stuck in her ears.
The Nightstalkers inform Blade that Dracula has been reawakened by the vampires in order to help with the vampire final solution, but they don't know what the final solution is. They do know, however, that they're going to need a new weapon, something bigger than silver nitrate bullets and garlic spray. Sommerfield is working on a biological weapon that she calls "DayStar," a virus that specifically targets vampires. Unfortunately, the virus' lethally is spotty. They need better DNA to work with. They need Dracula's blood because it's still pure, unaffected by generations of mutation. How to get to Drake?
Blade's idea is to go for the weakest link... the familiars. "Bleed the wannabees and they'll take us to the real", he says. So they take out a bunch of familiars. One of them gets a call on his cell phone as Blade is dangling him off the side of a bridge. Turns out to be Dr Vance, so they break into Vance's office to interrogate him. As they round the desk to directly approach Vance, they see the real Vance lying dead on the floor and realize that the "Vance" standing before them is actually Drake. Drake grabs King, stabs him, then jumps out the window, falling maybe 15 stories to the pavement below, landing feet first on a car roof, then running off park-our-style. Blade follows. They meet up again on the rooftops. Drake has carried a human infant he grabbed along the way and threatens to drop it some dozen or more stories to the pavement below. After slinging a few insults and threats back and forth, Drake tosses the baby over the gap between the buildings. Blade catches the baby, but Drake gets away.
While Abby stops the hemorrhaging in King's wound with an elastic protein, Sommerfield reveals that she has located the vampire's laboratory at Biomedical Enterprises. She also downloaded a copy of their recent purchases, like polymerase, bone marrow growth supplement, and genetic sequencing enzymes, so Blade and Abby decide to go snooping. While lurking outside, they see Chief Vreede drive up. A vampire comes out to meet him, and Blade and Abby pounce. After destroying the vampire, they force Vreede to take them inside the building. The first thing they see after turning on the lights is a huge warehouse filled with humans in stasis, all wired up as continuous blood donors. It's the vampire's final solution, Vreede explains. Instead of hunting blood on a piecemeal basis, the vampires have created a blood-farming facility. Blade shoots Vreede and forces the computer technician to shut down the facility.
Back at Honeycomb Hideout, Dex and Hedges are playing basketball, Sommerfield is reading a bedtime story to Zoe, and King is napping in the infirmary. Suddenly, Abraham Whistler appears to King. "Dude, you're dead", says King. It's not Whistler... it's Drake. When Blade and Abby return, they find Hedges, Dex, and Sommerfield dead. King and Zoe are missing. Drake has taken them back to the vampire's lair where King is now chained to the floor. He regains consciousness to stare eye-to-eye with a pomeranian. Suddenly the dog's lower jaw opens reaper-style. King manages to roll away just in time. Danica, Jarko, and Asher enter and take a few swipes at King. Then Danica asks King about the weapon that Blade is planning, but King refuses to talk so Danica threatens to turn him into a vampire again and wait until the thirst builds. Then... (door opens and in walk Drake and Zoe); "I'm going to bring the little girl in here for you" to feed on, Danica whispers into King's ear.
Fortunately, Sommerfield managed to get off a message to another Nightstalker named Caulder (Christopher Heyerdahl). Just before she was killed, Caulder tells them, Sommerfield developed a workable strain of the DayStar virus, and she transmitted the genetic sequence to him. It will need to be injected into Drake. If it is, it will mix with his blood and should kill every vampire in the area. However, Caulder adds, Sommerfield doesn't know whether it will kill Blade, too. Caulder has fashioned a projectile containing the DayStar virus. Abby loads it on one of the arrows to her compound bow. Now it's night-stalking time.
They have traced King's whereabouts by the tracking node implanted in his body. First, they pump atomized colloidal silver into the vampires' air conditioning system, which makes it difficult for the vampires to breathe. Then, Blade drops down through the skylight. While Blade takes on the vampires, Abby drops in and releases King. Then Abby pops in her MP3 earphones, and she and Blade take out a few dozen more vampires. King is chased by the vampire pomeranian and two vampire rottweilers, but he tricks them into leaping out a window. Abby rescues Zoe.
While King and Jarko go at each other with fists, Blade and Drake use swords. Abby takes out more vampires with her bow. King takes out Jarko, but Danica takes Jarko's place and she also dies. Drake has had enough of Blade and transforms into his monster self, complete with Reaper maw. Just when Drake is about to cream Blade, Abby shows up, loads the DayStar serum into her bow, and shoots it into the back of Drake's head. Drake pulls it out and tosses it on the floor, but Blade retrieves it and shoves the needle into Drake's chest. DayStar is released, dispersing the virus through the air, killing the rest of the vampires. When it's all over, Drake has become human again. Just before he dies, he compliments Blade on beginning a new race of vampires and reminds him that the thirst always wins.
Suddenly, dozens of FBI agents swarm into the building, only to find everything smashed to smithereens but no bodies other than Blade's. They transport him to the hospital and prepare to perform an autopsy. Just as they're about to make the first cut, Blade's body transforms into that of Drake. It was Drake's gift to Blade, knowing that Blade is the best hope for the vampire race of the future. Blade is still out there.
(In the unrated cut, as the FBI tries to do an autopsy on "Blade", Drake springs back to life, killing several of the autopsy members before ominously looming over one of the orderlies).
Hannibal closes the film with a final voice-over narration that the virus did not kill Blade as the human half of his heart did not stop beating, it only slowed down, causing him to enter into a comatose state until his body was ready to fight again. Blade awakens several months later ready to continue his war on all vampire-kind.