After the cruel lord Daigo Kagemitsu sells his newborn son's body parts to 48 demons in exchange for power, he casts what remains down a river and quickly forgets about his son, soon establishing a mighty kingdom. Little does Daigo know that his child survives, possessing advanced spiritual senses that allow him to navigate the world without eyes, ears, limbs, or even a voice.

A brilliant doctor rescues the son and raises him as his own, naming him Hyakkimaru and fitting him with advanced prosthetics that make it possible for him to move and fight. However, tragedy strikes when Hyakkimaru turns out to be a beacon that brings demons into the doctor's home, and the doctor eventually has to send Hyakkimaru out into the world.

Amid his travels, Hyakkimaru learns that slaying demons allow him to recover his missing parts and seeks to kill enough to make himself whole. He soon encounters Dororo—a boy claiming to be the world's greatest thief—who joins Hyakkimaru against his will in hopes of one day obtaining his sword. Together, the duo travels through a countryside infested with both demons and brutal men, who might prove to be worse.