Manji is an infamous swordsman in feudal Japan who is known as the "Hundred Man Killer," as he has killed one hundred innocent men. However, there is something far more frightening than his ominous reputation: the fact that he is immortal. This is the handiwork of eight-hundred-year-old nun Yaobikuni, who placed bloodworms capable of healing almost any wound in Manji's body. To atone for his crimes, Manji resolves to kill one thousand evil men. Yaobikuni agrees to this proposal, saying that if he succeeds, she will undo his curse of immortality. Soon after this promise, Manji meets Rin Asano, a 16-year-old girl who requests Manji's assistance in killing those who slaughtered her parents. Initially reluctant, Manji refuses Rin's desperate plea. However, owing to her evident lack of strength, Manji changes his mind and agrees to protect Rin for four years. With this partnership set in stone, the two embark on a perilous journey of bloodshed, vengeance, and redemption, each to fulfill their own life's cause.

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.

At the Battle of Sekigahara in 1600, Toyohisa Shimazu is the rearguard for his retreating troops, and is critically wounded when he suddenly finds himself in a modern, gleaming white hallway. Faced with only a stoic man named Murasaki and hundreds of doors on both sides, Toyohisa is pulled into the nearest door and into a world completely unlike his own. The strange land is populated by all manner of fantastical creatures, as well as warriors from different eras of Toyohisa's world who were thought to be dead. Quickly befriending the infamous warlord Nobunaga Oda and the ancient archer Yoichi Suketaka Nasu, Toyohisa learns of the political unrest tearing through the continent. Furthermore, they have been summoned as "Drifters" to fight against the "Ends," people who are responsible for the creation of the Orte Empire and are trying to annihilate the Drifters. As the Ends grow more powerful, so does the Empire's persecution of elves and other demihumans. It is up to Toyohisa and his group of unconventional heroes to battle in a brand-new world war to help the Empire's subjects, while protecting the land to claim for themselves and challenging the Ends.

Sentenced to death, ninja Gabimaru the Hollow finds himself apathetic. After leading a blood-soaked life, Gabimaru believes he deserves to die. However, every attempt to execute him inexplicably fails. Finally, Sagiri Yamada Asaemon, a fledgling member of a famed executioner clan, is asked to take Gabimaru's life; yet Sagiri makes no move to kill him as requested. Insisting that Gabimaru will not die because of his love for his wife, Sagiri instead offers him the chance to obtain a full pardon for his crimes. If he can travel to the island of Shinsekyo and obtain the Elixir of Life—which supposedly grants immortality—and bring it back for the shogun, then his freedom will be assured. But of the many who have traveled to Shinsekyo in search of the mythical Elixir, not a single person has returned sound of mind, if at all. Though unaware of the numerous dangers ahead, Gabimaru decides to accept the offer—alongside ten other death row convicts—in hope that he and his wife may finally live in peace.