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Blade forms an uneasy alliance with the vampire council in order to combat the Reapers, who are feeding on vampires.

A rare mutation has occurred within the vampire community. The Reaper. A vampire so consumed with an insatiable bloodlust that they prey on vampires as well as humans, transforming victims who are unlucky enough to survive into Reapers themselves. Now their quickly expanding population threatens the existence of vampires, and soon there won't be enough humans in the world to satisfy their bloodlust. Blade, Whistler and an armory expert named Scud are curiously summoned by the Shadow Council. The council reluctantly admits that they are in a dire situation and they require Blade's assistance. Blade then tenuously enters into an alliance with The Bloodpack, an elite team of vampires trained in all modes of combat to defeat the Reaper threat. Blade's team and the Bloodpack are the only line of defense which can prevent the Reaper population from wiping out the vampire and human populations.—Sean Daly

After the events with Deacon Frost, Blade continues to destroy as many vampires as he can. A new breed of super-vampire has appeared, which becomes an even greater threat than any evil currently out there. A group of high powered vampires, led by Nyssa and Asad request help from Blade in order to take down Nomak. Can Blade work alongside the very things he vowed to destroy?—Film_Fan

Two blood-soaked years after Deacon Frost's nightmarish plan in Blade (1998), the indestructible half-human/half-vampire hybrid, Blade, finds himself in the middle of an entirely different war. This time, both humankind and the vampire species are under attack, as a feral strain of insatiable blood-suckers named the Reapers feed on mortals and immortals alike. Under those dire circumstances, Blade reluctantly agrees to make an uneasy pact with his eternal adversaries, and lead an elite squad of vampire assassins against the mutual enemy. Can Blade avert the imminent advent of a horrifying new breed of undead predators?—Nick Riganas

Over the two years since the death of Deacon Frost, Blade (Wesley Snipes), has been trying to find his mentor Whistler (Kris Kristofferson), who was thought dead after being attacked by Deacon Frost, but was instead turned into a vampire and held prisoner by them for two years.

Blade is half-human, half-Vampire and is called "Day Walker" as he can survive in sunlight, which no other vampire can. Blade has all of the vampire strength and none of their weakness, except the thirst of blood. It was Whistler who cured Blade 20 years ago, taught him the rules and gave him the weapons to hunt with like silver, garlic and sunlight. Blade simulates sunlight in the form of UV ray bullets.

With the aid of Scud (Norman Reedus), his new weapon designer, Blade tracks Whistler to eastern Europe, where he is in possession of a large vampire gang. Blade attacks the gang and kills most of the members. Interrogating the last-surviving member, Rush (Santiago Segura), Blade finds Whistler locked in a water tank and kept alive to torture. Blade brings Whistler back to the lair and rids him of his Vampirism with a cure developed by Dr. Karen Jenson.

Meanwhile, a crisis has arisen in the vampire community. A mutated strain of Vampirism (dubbed the "Reaper virus"), originated from Jared Nomak (Luke Goss), is sweeping through their ranks. Nomak bears hatred toward the vampire race. Nomak was captured on camera when he attacked a blood bank.

The Reapers are stronger and much harder to kill than common vampires, being almost invulnerable to any weapon with the exception of sunlight. They also have a ravenous hunger, requiring more feeding than vampires, and anyone they bite, Human or Vampire, becomes a Reaper.

In order to combat the mutants, the vampire overlord (The ruling body of the Vampire nation) Eli Damaskinos (Thomas Kretschmann) sends his minion, Asad (Danny John-Jules), and daughter Nyssa (Leonor Varela) to find and strike a truce with Blade. After ascertaining that the Reapers are a threat to vampires and humans alike, Blade reluctantly allies with the vampires. He teams up with the Bloodpack, an elite group of vampires originally assembled to kill him. The group consists of Asad, Nyssa, Reinhardt (Ron Perlman), Chupa (Matt Schulze), Snowman (Donnie Yen), Verlaine (Marit Velle Kile), her lover Lighthammer (Daz Crawford), and Priest (Tony Curran). As Reinhardt openly challenges him to fight, Blade, in response, attaches an explosive to keep him in line.

The group starts at a vampire nightclub, while Whistler acts as a sniper to guard Scud in the team's transport. The group finds out that the Reapers are immune to silver, physically stronger than normal vampires, and resistant to normally crippling injuries. They are immune to most vampire weaknesses except for UV exposure. Priest is bitten, transformed and subsequently mercy-killed by exposure to sunlight; Lighthammer is bitten but conceals the bite.

Outside, Whistler disappears, and Scud is attacked by several Reapers, which he drives off with UV lights. Nomak arrives and tries to recruit Blade to his cause, but the latter refuses. Blade fights Nomak but cannot kill him due to his immunity to his weapons, including Blade's anti-coagulant spikes. After a stalemated battle, Nomak retreats because of the sunlight. Whistler returns after the battle and reveals his finding of the Reaper Nest down in the sewer. Nyssa dissects a dead Reaper to learn more about them; Scud and Whistler make ultraviolet weapons for the team.

Upon entering the Reaper nest, the group spreads out. Lighthammer transforms into a Reaper and kills Snowman. He then chases down Verlaine who kills both herself and him by exposing them both to sunlight.

Chupa turns on Whistler in retaliation for Priest's death, but Whistler secretly releases a cartridge of Reaper pheromones into the air, luring a horde that kills and devours Chupa. This attracts a horde which kills Chupa, while Whistler runs off.

Asad and Nyssa walk into a nest and Asad is pulled underwater and killed. Blade saves Nyssa and uses a UV-emitting bomb which destroys all of the Reapers with the exception of Nomak. Nyssa and Reinhardt manage to evade the blast, but Nyssa is seriously injured until Blade allows her to drink his blood to survive.

Damaskinos' forces betray and capture Blade, Whistler, and Scud. It is revealed that the Reapers exist as a result of Damaskinos' efforts to create a stronger breed of vampires. Nomak, the first Reaper, is his own son; and thus is Nyssa's brother. Scud is also revealed to be one of Damaskinos' familiars.

Scud reveals himself to be one of Damaskinos's familiars, but Blade, who already suspected this, kills him with the explosive he planted on Reinhardt earlier, which Scud originally thought was a dud until Blade secretly swapped it with a real explosive. Believing the Reapers are gone; Damaskinos plans to dissect Blade to learn the secret behind Daywalkers'. He traps Blade and begins draining his blood. Whistler escapes and frees Blade, killing Damaskinos' human lawyer Karel Kounen (Karel Roden) in the process. Whistler takes Blade to the Blood pool where Blade drinks the blood and restores his strength. Blade then fights his way through Damaskinos' henchmen and kills Reinhardt.

Meanwhile, Nomak enters Damaskinos' stronghold seeking revenge on his father. Nyssa, disillusioned with her father, betrays Damaskinos by sealing off their escape route to the heliport. Damaskinos is killed by Nomak after failing to negotiate with him. Nomak then bites Nyssa, infecting her with the Reaper virus.

Blade then confronts Nomak and the two engage in a brutal fight. Eventually, Blade fatally stabs Nomak in his only weak spot (which was found by Nyssa during the autopsy of reaper, which is the encased heart). With his revenge complete, and wanting to end the suffering, Nomak pushes the blade further in, killing himself.

Blade carries Nyssa outside, fulfilling her wish to see sunshine with her own eyes. She dies peacefully. With the crisis over, Blade goes to London where he tracks Rush down and kills him.