To aid his conquest of Japan, the ruthless lord Daigo Kagemitsu offers to sacrifice his soon-to-be-born son to 48 demons. The demons accept, and the next day, the child is born with several missing limbs and is ruthlessly cast down a river.

Fifteen years later, a stubborn young boy named Dororo struggles to survive against hunger and oppressive samurai on the streets of an impoverished and war-torn village. After angering a group of thugs, Dororo is attacked by them, but a mysterious man interrupts them, claiming to hear spirits nearby. Sure enough, a monster emerges from the river, and the man then removes his prosthetic arms, revealing blades hidden underneath, with which he slays the monster before leaving.

That night, as the man walks through the forest, Dororo approaches him and declares that he will accompany him. From this, the man, Hyakkimaru, reveals that many of his body parts were stolen by demons and that though he sought a peaceful life, he couldn't escape their relentless onslaught. Despite the tale, Dororo still insists on tagging along. And thus, Hyakkimaru travels through Japan with his new companion and a puppy named Nota, facing the brutality of both hell and mankind.