Set in the early 20th century during the aftermath of the Russo-Japanese War, "Golden Kamuy" centers on Saichi Sugimoto, a war veteran nicknamed "Sugimoto the Immortal" for his resilience in battle. Struggling to support the family of a deceased comrade, Sugimoto learns of a hidden fortune in gold stolen from the Ainu people, an indigenous group in Hokkaido. The treasure's location is encoded in a series of cryptic tattoos on the skins of escaped convicts. To find the gold, Sugimoto teams up with Asirpa, a young Ainu girl whose father was killed during the heist. Together, they embark on a perilous journey across Hokkaido, navigating harsh wilderness, rival treasure hunters, and the remnants of the 7th Division, a rogue military faction also seeking the gold.

The narrative intertwines historical and cultural elements, particularly through Asirpa's Ainu heritage, which is depicted with meticulous detail. Her knowledge of survival skills, hunting, and Ainu traditions becomes crucial to their quest. The story also introduces a diverse cast of characters, including Hijikata Toshizō, a former leader of the Shinsengumi, and his group of ex-samurai, who seek the gold to fund a rebellion. Other key figures include the cunning and ruthless Tsurumi, a disfigured lieutenant leading the 7th Division, and Shiraishi, a skilled escape artist who aids Sugimoto and Asirpa.

As the hunt for the tattooed skins intensifies, alliances shift, and betrayals abound. The series balances action, humor, and historical intrigue, often delving into the moral complexities of its characters. Themes of survival, cultural identity, and the consequences of greed are explored as the characters confront their pasts and motivations. The story's pacing alternates between intense confrontations and quieter moments that highlight the bond between Sugimoto and Asirpa, as well as the rich cultural backdrop of Hokkaido and the Ainu people. "Golden Kamuy" stands out for its unique blend of historical drama, adventure, and cultural exploration, making it a compelling and distinctive entry in the anime genre.