The story takes place in the mid-Muromachi period of ancient Japan, a turbulent and unstable era. A samurai named Takaeda Kagimitsu sought to make a name for himself in the chaotic Warring States period. To gain power and prominence, he made a "forbidden pact" with demons, offering his own son to 48 demon gods in exchange for power. The 48 demon gods each took one part from the infant's body, resulting in the child being born without 48 parts of his body. The heartless father then threw this severely deformed baby into a river, but fortunately, the baby was rescued by a doctor named Jikoku. The doctor created prosthetic replacements for all the missing body parts, gave him the name Hyakkimaru, and raised him.
Due to Hyakkimaru's unique constitution, he easily attracted malevolent spirits, endangering Dr. Jikoku who had raised him. Realizing that he posed a danger to others, Hyakkimaru decided to leave Dr. Jikoku and find a safe place where he could live in peace.
One night during his journey, while taking shelter in a cave, Hyakkimaru accidentally overheard a mysterious voice telling him that the 48 parts of his body were taken by 48 demon gods. To regain these missing parts, he would have to defeat all 48 demon gods. Thus, Hyakkimaru resolved to find and defeat these 48 demons, reclaim his body, and be reborn. Hyakkimaru began his quest for vengeance. Along the way, he accidentally saved a girl named Dororo, an orphan with a tragic past who had become a wandering thief in the tumultuous Warring States era. Dororo, insisting on calling Hyakkimaru her brother, claimed she wanted to obtain the demon sword on Hyakkimaru's body and followed him on his travels. Together, they embarked on a journey to slay demons, though Dororo’s reasons for following Hyakkimaru ran much deeper than initially revealed.