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.

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.

Daigo's castle is engulfed in flames. Within, two brothers by blood are at the mercy of fate. Dororo, Jukai and Lady Nui also head for the castle, each with their own thoughts weighing down upon their hearts. For a life that began with a silenced cry, where will the path of destiny lead?