"Sabikui Bisco" is set in a post-apocalyptic Japan where society has been ravaged by a mysterious phenomenon known as "Rust Wind," which corrodes everything it touches, including living organisms. The world is divided into harsh, desolate landscapes, and humanity struggles to survive amidst the environmental decay. Central to the story is the concept of "mushroomization," a process where humans and animals transform into fungal entities, further complicating the already dire situation.

The protagonist, Bisco Akaboshi, is a "Mushroom Keeper," a rogue figure who cultivates and wields mushrooms as weapons. Bisco is often misunderstood and labeled as a criminal due to his association with mushrooms, which are blamed for the spread of the Rust Wind. His primary goal is to find the legendary "Sabikui," a mushroom said to devour rust and potentially reverse the effects of the Rust Wind. Bisco’s journey is driven by a personal mission to save his mentor, Jabi, who has been afflicted by the Rust Wind.

Accompanying Bisco is Milo Nekoyanagi, a young doctor who initially opposes Bisco’s methods but eventually becomes his ally. Milo’s medical expertise and knowledge of the Rust Wind make him a valuable companion, and his perspective often clashes with Bisco’s more impulsive nature. Together, they navigate a world filled with hostile factions, mutated creatures, and the ever-present threat of the Rust Wind.

The narrative explores themes of survival, environmental collapse, and the clash between science and nature. As Bisco and Milo travel across the wasteland, they encounter various groups, including the authoritarian Imihama government, which seeks to control the remaining resources and suppress the Mushroom Keepers. The series delves into the moral ambiguities of survival in a decaying world, with characters often forced to make difficult choices.

Bisco’s quest for the Sabikui mushroom is fraught with challenges, including battles against powerful enemies and the unraveling of secrets about the true nature of the Rust Wind. The relationship between Bisco and Milo evolves from one of mutual distrust to a strong partnership, highlighting the importance of cooperation in the face of overwhelming adversity. The story balances action-packed sequences with moments of introspection, providing a multifaceted exploration of its post-apocalyptic setting and the characters’ struggles within it.