On the island nation of Hinomoto, humanity hides inside massive fortified stations to survive the Kabane, a race of undead creatures with glowing hearts protected by nearly impenetrable steel cages. Those bitten by a Kabane are doomed to rise again as one of the monsters, and the only way to kill them is to destroy their heart. In this steampunk world where armored steam locomotives called Hayajiro are the only means of transport between stations, a young steam smith named Ikoma has lost his sister to the Kabane and vows revenge. Living at Aragane Station, Ikoma secretly develops a powerful weapon called the Tsuranukizutsu, a piercing gun designed specifically to penetrate the Kabane heart cage, though his obsession leads others to mock him.

When a Hayajiro goes out of control and crashes into Aragane Station, the station is overrun by Kabane. During the chaos, Ikoma finally tests his weapon and succeeds in destroying a Kabane heart, but he is bitten in the process. Refusing to die, he strangles himself to prevent the virus from reaching his brain before it completes its transformation, emerging as a Kabaneri: a human-Kabane hybrid who possesses superhuman strength and healing abilities but must constantly fight the urge to crave blood. He boards the armored locomotive Koutetsujou, also known as the Iron Fortress, which is commanded by the young noblewoman Ayame Yomogawa and guarded by the skilled samurai Kurusu. On board, Ikoma meets a mysterious girl named Mumei, who is exempt from mandatory Kabane inspections and later reveals herself to also be a Kabaneri.

The story follows the survivors of Aragane Station as they journey across Hinomoto toward the shogunate capital of Kongoukaku, battling Kabane hordes while facing distrust from humans who fear the Kabaneri among them. Ikoma and Mumei struggle to prove their humanity while protecting the Iron Fortress from evolving Kabane variants such as Wazatori, which retain combat skills and intelligence from their former lives, and fusion colonies known as Black Smoke, formed from dozens of fused Kabane. The narrative builds toward a confrontation with Biba, a charismatic warlord who commands an army of Kabaneri and seeks to overthrow the shogunate, forcing the protagonists to choose sides in a conflict that blurs the line between monster and man.