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 Nui no Kata 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.

Itachi kidnapped Dororo and used the map on his back to lead them to Bone Cape. A mysterious boatman ferried them to the Cape but he had two demon sharks with him. One of the sharks ate half of Itachi's bandits while the other shark left with the boatman. However, Dororo and the remaining bandits managed to kill the shark. When the boatman and the second shark returned, Dororo was able to separate the boatman and the shark. Hyakkimaru arrived to stab the shark in one of its eyes, but It escaped. They held the boatman prisoner and then they landed on Bone Cape.

The boatman told the thirsty bandits of a spring not too far from their camp, and they went to drink, leaving Itachi, Dororo, the boatman and Hyakkimaru. Dororo later found their corpses and blood leading to the half-blind shark. Hyakkimaru killed the shark and the boatman, then recovered his real voice. Itachi went to search for the money but only found a letter from Hibukuro saying that he hid it somewhere else. The Magistrate arrived under the pretense of getting rid of the bandits but actually came for the treasure. Hyakkimaru, Dororo, and Itachi kill them, but Itachi was left for dead. Hyakkimaru and Dororo continued on their journey.

Sometime later Hyakkimaru learns that his father, Kagemitsu Daigo, was possessed by the 48 demons, and went to slay him. Things were going badly on the Daigo clan's land, and the citizens were forced to build a fort for him. The slaves were planning a rebellion, but one of the slaves told Kagemitsu of their plans, and he was prepared. His archers shot and killed many slaves and the remainder hid in a tunnel they had built under the fort.

Hyakkimaru left Dororo and ran into the fort. Dororo joined the slaves in their ambush, but Kagemitsu Daigo's soldiers caught Dororo. To prove his loyalty, Kagemitsu told Hyakkimaru to kill Dororo. Hyakkimaru acted as if he was about to kill Dororo but turned around and threw his sword into the dark stabbing the physical manifestation of the 48 demons, however, some of them managed to escape. The slaves charged through the tunnel and attacked Kagemitsu's soldiers. Kagemitsu, weak because of the slain demons, escaped with his wife Nui.

After he regained his eyes, Hyakkimaru figured out that Dororo is female, though Dororo rejects the notion and refers to himself as a boy despite Hyakkimaru's insistence to act more feminine. This is in part due to Dororo being raised as a boy by his parents in order to be tough. Hyakkimaru also wanted Dororo to fight with the farmers against those in power because Dororo's father was a farmer. Hyakkimaru gave his sword to Dororo, the one that he had desired throughout the series. Hyakkimaru planned to continue his journey alone, agreeing to meet Dororo again when Hyakkimaru's body was whole. They parted with Dororo crying at the doors. It wasn't until 50 years later that the last of the 48 demons was slain. 


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