Dororo and Hyakkimaru come across an abandoned, burnt-out temple, where they meet a man named Sabame who rules the surrounding area. Sabame invites the two of them to his residence and tells them the story behind the burnt-out temple and the ghoul that haunts it. However, Dororo and Hyakkimaru suspect that he might not be telling the truth.
The spider-like ghoul Jorogumo is wounded by Hyakkimaru. To heal itself, it transforms into a woman and takes advantage of the hospitality of a young man named Yajiro. Having let Jorogumo slip through their fingers, Dororo and Hyakkimaru stop at a village where they hear rumors of a kidnapper at large.
Struggling to adapt to an unfamiliar world of "sound", Hyakkimaru is injured in a fight with a ghoul. He is taken in and nursed by a girl named Mio, who looks after children orphaned by war. However, after becoming aware of a demon nearby, Hyakkimaru heads out to fight it before he is fully recovered.
Jukai is a doctor who travels the land fitting prosthetic arms and legs to those who have lost their limbs in war. One day, on the riverbank he finds a baby missing most of its body parts. He decides to raise the child, who he names “Hyakkimaru”. Jukai provides the child with prostheses, but the time comes when Hyakkimaru sets out on a journey to recover his own body parts.
In Japan's Warring States period, Lord Daigo Kagemitsu makes a pact with 12 demons, offering them his unborn son in exchange for the prosperity of his lands. Years later, young thief Dororo is attacked by a ghoul but rescued by a mysterious boy, whose body parts turn out to be almost entirely prosthetic.