Buso Renkin is the story of teenager Kazuki Muto, who dies trying to save a girl who was being attacked by an eerie monster. The next morning, however, Kazuki is left wondering whether it was all a dream. Lo and behold, the girl, the monster, and his death are all real! The girl, Tokiko Tsumura, was actually trying to slay the homunculus (a beast that can take the form of humans, and whose main source of food is people), but Kazuki got in her way. To revive Kazuki, Tokiko replaces his heart with a "kakugane," an alchemic device that allows him to summon a lance with which to fight the monsters. It turns out that Tokiko is a member of the Alchemist Warriors, an organization sworn to protect the world from the diabolical creatures. Soon, Kazuki joins Tokiko in her quest to terminate the sinister being that creates and controls the homunculus.

Upon arriving at the hidden headquarters of the League of Extraordinary Elects (the L.X.E.), the Alchemist Warriors learn of the League's plot to attack the high school. Kazuki and Tokiko immediately head over there, only to discover that the school has been surrounded by Doctor Butterfly's newly created humanoid homunculus soldiers. To the Alchemist Warriors' surprise and dismay, they find that not only are they facing Doctor Butterfly's minions, but the students of the school as well!