During a tumultuous period in Japan's history, Lord Daigo Kagemitsu's selfish pact with demons results in his son, Hyakkimaru, being born with deformities; years later, a teenage Hyakkimaru saves a young theif named Dororo from a ghoul.

Dororo and Hyakkimaru arrive in a village seeking protection from a demon, but Hyakkimaru's threatening actions toward the village's chief land the duo in prison.

A doctor named Jukai comes upon the abandoned infant Hyakkimaru and decides to raise him and outfit him with prosthetic limbs.

Hyakkimaru encounters the deadly Tanosuke the Slaughterer and his demon-possessed sword, which takes control of Dororo.

Hyakkimaru, badly wounded from an altercation with a monster, receives care from a woman who took a group of orphans under her wing, but Hyakkimaru's obsession for slaying demons conflicts with his need to rest and recover.

Hyakkimaru bonds with Mio as he prepares for a rematch with the demon who wounded his leg.