"Black Bullet" is set in a dystopian future where humanity is on the brink of extinction due to the emergence of parasitic creatures known as Gastrea. These creatures, which originated from a meteorite, infect hosts and mutate them into monstrous forms, leading to widespread destruction. In response, humanity has developed a vaccine to prevent infection, but it only works on young girls. These girls, known as Cursed Children, gain enhanced physical abilities but are ostracized by society due to their association with the Gastrea.

The story centers on Rentaro Satomi, a young civil officer tasked with protecting Tokyo from Gastrea threats. Rentaro is a skilled fighter equipped with a mechanical arm and leg, the result of injuries sustained in battle. He partners with Enju Aihara, a Cursed Child with superhuman strength and agility. Together, they work as part of a private security force to combat Gastrea incursions and maintain order in a fractured world.

As the narrative progresses, Rentaro and Enju uncover a conspiracy involving the Gastrea and the government. They learn that the Gastrea are not merely mindless monsters but are part of a larger, more sinister plan. The duo faces numerous challenges, including battles with powerful Gastrea, political intrigue, and the moral dilemmas surrounding the treatment of Cursed Children. Their journey reveals the complexities of a society struggling to survive while grappling with fear, prejudice, and the ethical implications of using children as weapons.

Key characters include Kisara Tendo, Rentaro's childhood friend and the head of the Tendo Civil Security Agency, who provides strategic support and resources. Tina Sprout, another Cursed Child, initially appears as an antagonist but later becomes an ally. The series explores themes of survival, sacrifice, and the blurred lines between humanity and monstrosity, set against a backdrop of constant danger and societal collapse.