Daigo Kagemitsu, who works for a Samurai general in Japans Warring States period, promises to offer 48 body parts of his unborn baby to 48 devils in exchange for complete domination of the country. When the baby boy is born, Daigo has him thrown into a river, hoping the boy will die. A kind sage, however, finds him and adopts him. The sage fits out his poor son with prosthetics.

Time goes by and the baby grows into a boy who calls himself Hyakkimaru. Everytime Hyakkimaru eliminates a devil, he retrieves one of his missing body parts. Hyakkimaru meets a boy thief named Dororo and together they travel the countryside in search of the devils who possess Hyakkimarus parts. Throughout their travels, they face monsters and ghosts.