In an abandoned factory at night, Kazuki Muto dies in an attempt to save a girl from a monster. Or does he? Kazuki wakes up the next morning as if nothing happened. But after school, when his teacher transforms into that same monster, Tokiko, the girl he tried to save the previous night, appears and tells him that the monster is a homunculus and that he did in fact die the night before! But Tokiko replaced his heart with an alchemical alloy called a kakugane that can transform into a weapon of immense power called a Buso Renkin. Now, Kazuki is about to find himself mixed up in a supernatural battle!

Tokiko and Kazuki visit the haunted factory where everything began. There, they find the remains of victims and a homunculus incubator. The homunculi made there lodge themselves onto humans and consume them, creating monsters like the one that attacked Kazuki. But who is doing this, and why? Before they can begin their search, Kazuki and Tokiko are attacked from above by a homunculus with giant eagle wings carrying a man in a school uniform on his back.

A homunculus embryo has lodged itself on Tokiko, and a week remains before she becomes a homunculus. Between bouts of training with his lance, Kazuki and Tokiko search for the creator of homunculus in order to obtain the antidote. Meanwhile, the Papillon Masked Creator orders his subordinate homunculus Kawazui to find the lance-wielding boy. Kawazui's desire for revenge makes Kazuki hold even tighter to his personal vow: to use the kakugane Tokiko gave him not for himself but to protect others. His first one-on-one battle with a homunculus begins!

Kazuki and Tokiko search for a student who has been absent from school for the past four days and come across a sickly third-year student who turns out to be the creator of the homunculi, Koshaku Chono. Chono explains that he has an incurable illness and used his ancestor's research on alchemy to gain the technology to produce homunculi and eventually reach his goal of attaining an immortal body by becoming a humanoid homunculus. Tokiko is outraged that Chono is willing to sacrifice other lives in order to defy his own death and tries to destroy the core homunculus made from Chono’s own cells.

Evading the homunculus Washio's attack, Kazuki and Tokiko fall back to form a plan. The two devise a series of high-speed attacks, but Washio's natural instinct and warrior experience sees through their plan. He slashes Tokiko, and Kazuki succeeds in delivering a single blow to Washio. But Tokiko is heavily wounded, and worse, the lodged homunculus has progressed up to her spinal cord. Kazuki fights on, and Washio feels a stubborn strength growing within the boy.

Seeking the antidote, Kazuki goes to Chono's house, where Chono's father tells him he has cut ties with his son. Kazuki heads to the warehouse behind the Chono household, the very place where his ancestor conducted his alchemy research, where Chono is waiting alone for the core homunculus to hatch. Chono welcomes Kazuki and says he will give him the antidote but will not hand over the homunculus, his only chance for survival. Kazuki advises Chono that whether he’s human or homunculus, he will die alone, though Chono doesn't seem to care.