"Sabikui Bisco" is set in a post-apocalyptic Japan where a mysterious rusting disease, known as the Rusting Wind, has devastated the land, turning everything it touches into corroded ruins. The story centers on Bisco Akaboshi, a skilled archer and outlaw known as the "Man-Eating Mushroom," who is on a quest to find the mythical Sabikui, a mushroom said to cure the Rusting Wind. Bisco is accompanied by Milo Nekoyanagi, a young doctor who initially captures him but later becomes his ally. Together, they navigate a world filled with dangerous creatures, corrupt authorities, and rival factions, all while uncovering the truth behind the Rusting Wind and the origins of the Sabikui.

The narrative explores themes of survival, environmental decay, and the clash between nature and industrialization. Bisco and Milo's journey takes them through various regions, each with its own challenges and inhabitants, including the militaristic Imihama Prefecture, which seeks to control the remaining resources. The duo faces opposition from powerful enemies, such as the ruthless Governor Kurokawa, who has his own agenda tied to the Rusting Wind. As the story progresses, Bisco and Milo's partnership evolves, revealing deeper layers of their personalities and motivations.

The series balances action, adventure, and character development, with a focus on the dynamic between Bisco's rugged, survivalist nature and Milo's compassionate, scientific approach. The world-building is intricate, presenting a dystopian landscape where humanity struggles to adapt to the ecological collapse caused by the Rusting Wind. The plot is driven by the protagonists' quest for the Sabikui, but it also delves into the broader implications of the disease and the societal structures that have emerged in its wake. "Sabikui Bisco" offers a compelling blend of post-apocalyptic storytelling, unique lore, and a central mystery that keeps the narrative engaging throughout.