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.

In early 1900s Hokkaido after the Russo-Japanese war, Saichi Sugimoto tirelessly pans for gold. Nicknamed "Sugimoto the Immortal" for his death-defying acts in battle, the ex-soldier seeks fortune in order to fulfill a promise made to his best friend before he was killed in action: to support his family, especially his widow who needs treatment overseas for her deteriorating eyesight. One day, a drunken companion tells Sugimoto the tale of a man who murdered a group of Ainu and stole a fortune in gold. Before his arrest by the police, he hid the gold somewhere in Hokkaido. The only clue to its location is the coded map he tattooed on the bodies of his cellmates in exchange for a share of the treasure, should they manage to escape and find it. Sugimoto does not think much of the tale until he discovers the drunken man's corpse bearing the same tattoos described in the story. But before he can collect his thoughts, a grizzly bear—the cause of the man's demise—approaches Sugimoto, intent on finishing her meal. He is saved by a young Ainu girl named Asirpa, whose father happened to be one of the murdered Ainu. With Asirpa's hunting skills and Sugimoto's survival instincts, the pair agree to join forces and find the hidden treasure—one to get back what was rightfully her people's, and the other to fulfill his friend's dying wish.

In Hokkaido, it is rumored that there is a stash of hidden gold. This gold was supposedly stolen by a man who killed the original Ainu owners; and before being captured and imprisoned by the police, he hid it in a secret location. In order to relay the gold's location to his comrades on the outside, he tattooed the map on the bodies of his cellmates and promised them a share of the gold—provided they managed to escape and find it. In Golden Kamuy 2nd Season, First Lieutenant Tokushirou Tsurumi plans to give the 7th Division an advantage in the war for the tattoos by getting a taxidermist to create skins that only he can distinguish as fake. Meanwhile, Saichi "The Immortal" Sugimoto, Asirpa, and their companions continue their hunt for the skins by following a strange rumor: a thief who broke into a home in Yubari found taxidermied human corpses, among which was a torso with strange tattoos.

After obtaining information about Asirpa from the foreteller Inkarmat, Saichi "The Immortal" Sugimoto, Genjirou Tanigaki, and Cikapasi join the Seventh Division's Otonoshin Koito and Hajime Tsukishima on a journey to Karafuto. Heading further north into the freezing Russian territory, they collect any clues about Asirpa's whereabouts they can find and rush after her. Meanwhile, Asirpa is unaware of what truly transpired at Abashiri Prison. Deeply disturbed and confused by her father Wilk's past actions, Asirpa follows his old friend Kiroranke to the place where Wilk was born and raised in order to better understand his motives. However, Kiroranke and the master sniper Hyakunosuke Ogata are scheming behind her back. Even if they were to obtain all 24 tattooed skins that form a map to the lost Ainu gold, the various factions searching for it now understand that the map is useless without Asirpa. Realizing the danger she could be in, Sugimoto desperately hopes to reach Asirpa first and protect her from the greedy clutches of those who plan to drag her into their sins.