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.

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.

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.

Dororo has been captured by Itachi and is being taken to the cape where Hibukuro supposedly hid the money. As Itachi and his men look for boats to get across to the cape, they are approached by a one-armed boy named Shiranui.

While traveling along a mountain path in search of a demon, Dororo and Hyakkimaru encounter a young man named Dice-spot Saburota. The man says that he too is hunting the demon, and they set off to exterminate it together.