The narrative of Buso Renkin follows Kazuki Muto, who saves Tokiko Tsumura and is killed by an alchemical monster known as ahomunculus. Tokiko, an alchemist warrior, feels responsible and revives him by replacing his destroyed heart with a kakugane (核鉄). The kakugane is an alchemical device which, when activated, takes a weapon form based on its user's personality, forming a buso renkin—the only thing that can destroy a homunculus. Kazuki creates his own buso renkin and joins Tokiko in the fight against the homunculi and their master, Koushaku Chouno. Chouno, who has renamed himself "Papillon", is killed by Kazuki, but is later resurrected by the L.X.E., a humanoid homunculi group led by Chouno's great-great-grandfather Bakushaku Chouno, now calling himself Dr. Butterfly. In various battles, Kazuki, Tokiko and Captain Bravo (their team leader) destroy most of the L.X.E.'s members. After learning that Dr. Butterfly believes him to be weak and useless, Papillon rebels against the L.X.E. and kills Dr. Butterfly.

Before his death, Dr. Butterfly drains the energy of the students at Kazuki's school to heal and revive Victor, a being superior to humans and homunculi. Victor is confronted by Kazuki, but Victor is not interested in fighting and leaves. During the battle, however, Kazuki's kakugane is revealed to be the same type as the Victor's—a black kakugane created by the Alchemist Army as a prototype to the philosopher's stone. The black kakugane absorbs human life forces; to prevent this from happening, Kazuki's death is ordered by the Alchemist Army. Captain Bravo tries to kill Kazuki, but Tokiko finds him alive. A team is commissioned to confirm Kazuki's death, but Kazuki, Tokiko and Gouta Nakamura (an Alchemist Warrior and former protégé of Tokiko's) fight their way past the members of the Re-Extermination Squad. Later, Kazuki's death is postponed because, as the Alchemists' leader explains, their top priority is to defeat Victor.

Kazuki and Tokiko find the white kakugane, which can negate the effects of the black kakugane and is guarded by Victor's daughter Victoria, who is herself a humanoid homunculus. During the Alchemist Army's final battle against Victor, Kazuki applies the white kakugane to Victor, but it only weakens him. To protect humankind from both of them, Kazuki propels himself and Victor to the moon. Later, Papillion creates a white kakugane to heal Kazuki. The Alchemist Army rescues Kazuki, creates another white kakugane and restores Victor's humanity. Reunited with his daughter, Victor asks the Alchemist Army to turn him into a homunculus and tells them that he and his daughter will lead all the homunculi to the moon. The Alchemist Army dedicates itself to research a way to revert homunculi back into humans, ending their war activities. All Warriors abdicate their kakugane. Kazuki and Tokiko return to their daily lives together while Papillon becomes an urban legend throughout Japan.