The story takes place in the mid-Muromachi era of ancient Japan, a turbulent age filled with constant warfare. A samurai named Tengu Seikou, in his ambition to rise above others in the chaotic Warring States period, makes a "forbidden pact" with demons, offering his own son to 48 demons in exchange for power. The 48 demons each take a part of the infant's body, resulting in the child being born without 48 parts of his body. The heartless father then discards this severely deformed infant into a river, but he is luckily rescued by a doctor named Jikoku. The doctor creates prosthetics for all the missing parts of the baby’s body, names him Hyakkimaru, and raises him.
Due to Hyakkimaru's unique constitution, he easily attracts malevolent spirits, which pose a danger to Jikoku who has raised him. Realizing that he could be a threat to others, Hyakkimaru decides to leave Jikoku and find a safe place for himself. One night during his journey, while resting in a cave, Hyakkimaru overhears a mysterious voice telling him that the 48 parts of his body were taken by 48 demons, and he must defeat these demons to regain them. Determined, Hyakkimaru sets out on a mission to find and conquer the 48 demons, reclaim his body, and be reborn.
On his journey, Hyakkimaru accidentally rescues a girl named Dororo. Dororo is an orphan with a tragic past, reduced to thievery in the tumultuous Warring States era. Insisting that Hyakkimaru be her older brother, she claims she wants the demon sword from Hyakkimaru's hand and continues to travel with him. Together, they embark on a quest to slay demons. However, Dororo's insistence to follow Hyakkimaru has deeper reasons than what meets the eye.