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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.

Dororo and Hyakkimaru happen upon a village and are brought before its chief, Lady Bandai. However, Hyakkimaru inexplicably draws his sword in her presence, resulting in both him and Dororo being locked in a storehouse by the villagers. It turns out they are not the only ones confined there...

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.

Dororo and Hyakkimaru come face to face with Tanosuke the Slaughterer, who wields a cursed sword in which a demon dwells. Hyakkimaru narrowly manages to repel Tanosuke, but the demon blade falls into Dororo's hands and begins to take control of him.

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.

Hyakkimaru regained his voice in a fight with a demon, but lost his leg in the process. After returning to the run-down temple to allow his wounds to heal, he once again sets out to confront the demon. Meanwhile, Mio and the children wait at the temple but...

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.

At a certain village, young girls are offered up as ritual sacrifices to appease a giant centipede demon that appears shrouded in black clouds. Hyakkimaru and Dororo team up with Saru, a boy whose older sister has been offered as a sacrifice, and together they confront the demon.

Dororo comes down with a high fever. While woozy from its effects, the youngster catches a glimpse of some red spider lilies, which stirs up memories of past days spent with parents Hibukuro and Ojiya.

A village within Daigo's domain is being terrorized by a ghoul that dwells in a nearby lake. Tahomaru, accompanied by his aides Hyogo and Mutsu, volunteers to exterminate the ghoul.

After entering Lord Daigo's domain, Dororo and Hyakkimaru hear tales of Banmon, the huge wall that is the last remnant of a fort that once stood on the border. Hyakkimaru squares off against the fox demon that haunts the wall.

Kagemitsu, who offered up his own son to the demons. Hyakkimaru, who is trying to get back the body parts that were taken from him. As if drawn together by fate, they face each other.

Having left Daigo's domain, Dororo finds a statue of Fudo, one of the wisdom gods. But the statue is actually a demon that is harvesting humans' faces in an attempt to find one for itself.