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...

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 has regained his voice from the devil god, but one leg was stolen from him. After returning to the deserted temple and having his wounds taken care of, he again goes into battle with the demon. Meanwhile, in the abandoned temple where Mio and the children are waiting ...

Jukai is reunited with a bloodied Hyakkimaru at the site of a recent battle, and finds out the truth of how Hyakkimaru and the demons are connected. Hyakkimaru asks Jukai for a new prosthetic leg, but...

Hyakkimaru comes face to face with Tahomaru, Mutsu and Hyogo, who have been possessed by the power of demons. Dororo, Lady Nui and Biwamaru hurry to the scene, where they witness a ferocious battle that will determine the future of the land of Daigo.

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?