Dororo revolves around a rōnin named Hyakkimaru (百鬼丸) and young orphan thief named Dororo (どろろ) during the Sengoku period. The rōnin was born malformed, limbless and without facial features or internal organs. This was the result of his birth father daimyō Kagemitsu Daigō forging a pact with 48 sealed demons so that he might rule the land and increase its wealth and prosperity. In return, he promised the demons anything that they wanted which belonged to him. This enabled them to roam free and commit atrocities along the countryside.
After his mother Oku was forced to set him adrift on the river, lest he be killed by his father, the infant was subsequently found and raised by Jukai-sensei, a medicine man who used healing magic and alchemical methods to give the child prostheses crafted from the remains of children who had died in the war. The boy became nearly invincible against any mortal blow as a result of the prostheses and healing magic. Grafted into his left arm was a very special blade that a traveling storyteller presented to Jukai-sensei, believing it was fated to be within his possession given that ever since the boy had been discovered, the doctor had been visited by goblins. As revealed in a short tale about the blade's origin, the blade had been forged out of vengeance to kill goblins as well as other supernatural entities.
After the sensei was forced to send him on his way because he was attracting demons, the young man learned from a ghostly voice of the curse that had been set upon him at birth and that by killing the demons responsible he could reclaim the stolen pieces of his body and thus regain his humanity. Across his travels, he earned the name "Hyakkimaru" (百鬼丸) among other names for his inhuman nature. On one such hunt of a demon, Hyakkimaru came across a young orphan thief named Dororo who thereafter travels by his side through the war-torn countryside. When Hyakkimaru met Dororo, he had already killed 15 demons.
Throughout their journey, Hyakkimaru killed 6 more demons, bringing the total to 21. Along the way, Hyakkimaru learns that Dororo was hiding a big secret. Dororo's father, Bandit Hibukuro, hid money he saved up on his raids on Bone Cape to later be distributed to the people squeezed dry by the samurai. Itachi, a bandit who betrayed Hibukuro and sided with the authorities, crippled Hibukuro. Hibukuro escaped with limping legs, along with his wife and young Dororo. Hibukuro dies trying to let his family escape. Fearing that she will die, Dororo's mother prayed to Buddha and, with her blood, drew the map that will lead him to Bone Cape. Three days later, she froze to death.