The greedy samurai lord Daigo Kagemitsu's land is dying, and he would do anything for power, even renounce Buddha and make a pact with demons. His prayers are answered by 12 demons who grant him the power he desires by aiding his prefecture's growth, but at a price. When Kagemitsu's first son is born, the boy has no limbs, no nose, no eyes, no ears, nor even skin—yet still, he lives.

This child is disposed of in a river and forgotten. But as luck would have it, he is saved by a medicine man who provides him with prosthetics and weapons, allowing for him to survive and fend for himself. The boy lives and grows, and although he cannot see, hear, or feel anything, he must defeat the demons that took him as sacrifice. With the death of each one, he regains a part of himself that is rightfully his. For many years he wanders alone, until one day an orphan boy, Dororo, befriends him. The unlikely pair of castaways now fight for their survival and humanity in an unforgiving, demon-infested world.

Surrounded by a forest and a gated entrance, the Grace Field House is inhabited by orphans happily living together as one big family, looked after by their "Mama," Isabella. Although they are required to take tests daily, the children are free to spend their time as they see fit, usually playing outside, as long as they do not venture too far from the orphanage—a rule they are expected to follow no matter what. However, all good times must come to an end, as every few months, a child is adopted and sent to live with their new family, never to be heard from again.

However, the three oldest siblings have their suspicions about what is actually happening at the orphanage, and they are about to discover the cruel fate that awaits the children living at Grace Field, including the twisted nature of their beloved Mama.