Disguising themselves as humans, homunculi inhabit the world to prey on the unsuspecting population. Created long ago by alchemists from Europe, homunculi are difficult to eliminate without weapons known as Kurogane. Each Kurogane is uniquely shaped according to its wielder's instincts, taking the form of special abilities called Busou Renkin.

While walking home from school one day, Kazuki Mutou spots a defenseless girl under attack by a homunculus. But as he attempts to intervene, the girl ends up saving Kazuki’s life instead, shattering his ignorant worldview. The girl introduces herself as Tokiko Tsumura, and Kazuki soon learns that she has accidentally implanted a Kurogane inside of him. Now unintentionally dragged into the fight against homunculi, Kazuki must forgo his former life of leisure in order to protect the ones he holds dear.