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.

To fix Hyakkimaru's broken sword, he and Dororo travel to a village where a master swordmaker named Munetsuna lives. Upon arriving at Munetsuna's house, they are met by his daughter Okowa.

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?