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.

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.

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.

Sabame has been feeding people to the demons to protect the village over which he rules. As Hyakkimaru once again confronts the demon moths, Dororo gets trapped in a storehouse.

The shark demon lets out a roar and attacks Dororo, who is tied up and unable to move. Meanwhile, a troop of soldiers commanded by Tahomaru is also approaching the cape.

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 Kagemitsu continues to prepare for war with the neighboring land of Asakura. Upon receiving word that Hyakkimaru is approaching his domain, Kagemitsu sends Tahomaru to dispose of him.

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?