In the 11th year of the Meiji Era, the end of the samurai shogunate and the prohibition of swords has left Japan with lasting scars. Displeased by these recent changes, many former samurai plot against the new government, inciting a wave of bloodshed. To counter this movement, the government constructs a colossal prison in the middle of Lake Biwa. Unofficially assigned to help the police arrest criminals, Tenka Kumou also serves as a ferryman to the Lake Biwa prison with the help of his two younger siblings: the ambitious Soramaru and the enthusiastic Chuutarou. Together with the former Fuma ninja Shirasu Kinjou, the Kumou brothers live a frugal and joyful life mostly dedicated to studying and training. However, behind this relatively uneventful daily routine, the specter of the Orochi curse is starting to spread its shadow over the city of Oumi. According to legend, every three hundred years, Orochi reincarnates in a human vessel—and it is believed that this is the harbinger of an imminent catastrophe. As various groups clash in search of Orochi's vessel, some aim to seal the curse, while others have darker plans in motion.

Hole—a dark, decrepit, and disorderly district where the strong prey on the weak and death is an ordinary occurrence—is all but befitting of the name given to it. A realm separated from law and ethics, it is a testing ground to the magic users who dominate it. As a race occupying the highest rungs of their society, the magic users think of the denizens of Hole as no more than insects. Murdered, mutilated, and made experiments without a second thought, the powerless Hole dwellers litter the halls of Hole's hospital on a daily basis. Possessing free access to and from the cesspool, and with little challenge to their authority, the magic users appear indomitable to most—aside for a few. Caiman, more reptile than man, is one such individual. He hunts them on a heedless quest for answers with only a trusted pair of bayonets and his immunity to magic. Cursed by his appearance and tormented by nightmares, magic users are his only clue to restoring his life to normal. With his biggest obstacle being his stomach, his female companion Nikaidou, who runs the restaurant Hungry Bug, is his greatest ally.

Dorohedoro: Ma no Omake further explores the world of sorcerers and the Hole, honing in on what the characters do in their spare time when they are not seeking out their enemies. Kamen Kakusa Fujita attends a mask conjuring ritual in hopes of a Devil bestowing him with an appropriate mask, like the ones his colleagues Noi and Shin possess. Hopefully his offering entices the mask-maker! Tenpo For You Nikaidou, lacking money and forced to sell gyoza on the streets of the Hole, stumbles upon a quaint shop selling tea and sweets. Its owner is the gentle and hospitable Syueron, but it seems the denizens of the Hole bear a grudge against him. Shitappa Seishun Graffiti Intrigued by the photographs hanging around the mansion, Ebisu approaches En hoping for a portrait of her own. However, she is disappointed to find that only members of the En Family can have their pictures taken. Anata no Shiranai Gyoza no Kai The Gyoza Fairy keeps the Hungry Bug in pristine condition, but his primary responsibility is ensuring the gyoza tastes good. So he becomes rather agitated when Nikaidou's customers do not properly enjoy their meals. Odoru Ma no Utage En is enthusiastic about his masquerade ball and is adamant on his family's participation. Per tradition, attendees must choose a partner and dance to appease the Devils. To their horror, they discover that failing to do so may incur nasty consequences! Yokaze ni Fukarete Ooba Kinenbi Nikaidou gives detailed instructions on preparing oba gyoza and Kaiman is eager to help!

The greedy samurai lord Daigo Kagemitsu's land is dying, and he would do anything for power, even renounce Buddha and make a pact with demons. His prayers are answered by 12 demons who grant him the power he desires by aiding his prefecture's growth, but at a price. When Kagemitsu's first son is born, the boy has no limbs, no nose, no eyes, no ears, nor even skin—yet still, he lives. This child is disposed of in a river and forgotten. But as luck would have it, he is saved by a medicine man who provides him with prosthetics and weapons, allowing for him to survive and fend for himself. The boy lives and grows, and although he cannot see, hear, or feel anything, he must defeat the demons that took him as sacrifice. With the death of each one, he regains a part of himself that is rightfully his. For many years he wanders alone, until one day an orphan boy, Dororo, befriends him. The unlikely pair of castaways now fight for their survival and humanity in an unforgiving, demon-infested world.