Japan has become a wasteland devastated by the Rusty Wind which causes all things to rust away. A suspicious looking priest visits a checkpoint all alone, yet on his back rests a bow priests wouldn't use. Meanwhile, Milo, a doctor running a clinic in the town of Imihama, is researching new medicines in secret in order to save his older sister, Pawoo, who's being corroded by the Rust. But that day a stranger appears before him...

The wanted criminal, Akaboshi Bisco, causes havoc in the town of Imihama using his bow to cause giant mushrooms to bloom. Bisco searches for a doctor who can synthesize medicine to save his mentor, Jabi, who has become gravely ill. Bisco storms into the clinic and accosts Milo, but Governor Kurokawa hears the commotion and dispatches his elite forces.

Bisco and Jabi continue their journey through Touhoku in search of Sabikui, the Rust-Eater, a mushroom said to cleanse away any rust. Milo also realizes that if he could cure his sister, Pawoo, if he had this Rust-Eater. Meanwhile, the governor of Imihama, Kurokawa, burns with an unusual obsession with killing Bisco.

Milo and Bisco head toward Touhoku in search of the legendary mushroom, Rust-Eater. After reuniting with their friend, the giant crab Actagawa, Milo struggles with his training to ride the crab, but ends up communicating with it thanks to his kindness. That night the two of them try to rest at the Nikkou War Memorial only to reunite with a jellyfish girl they met in Imihama.

On their way to Akita, Bisco and Milo pass by the sea of Calbero and arrive at a desolate town under threat from the deadly creatures, Flying Blowfish. A town that's also full of children and devoid of adults. Meanwhile, Pawoo encounters a mysterious couple living in some ruins as she pursues the others.

With the information obtained from Tetsujin Town, Bisco and Milo continue to head north. As they make their way through Shimobuki Prefecture, the land encased in snow, they encounter Tirol, nearly frozen to death. With Tirol's aid, the two continue their journey toward their final destination - Konakidani, the land said to contain the Rust Eater.

Bisco and Milo finally reach Konakidani when the Pipe Snake, a divine beast with two heads that's the size of a dragon, appears before them. That's also when Pawoo catches up to them with the worst possible timing. Soon enough, even Pawoo is dragged into the intense battle against the Pipe Snake. Meanwhile, Kurokawa also closes in around them...

Bisco is gravely wounded by the shot from Kurokawa. Milo leaves him behind to storm into enemy territory and rescue his captured friends, Pawoo and Jabi, but Kurokawa awaits with meticulously set traps. During their confrontation Kurokawa reveals his great ambition and the secret behind the Mushroom Keeper's persecution.

Milo is left standing at death's door by Kurokawa's traps. Kurokawa has once again captured Jabi, and this time he shares a glimpse of his terrifying plan to utilize Tetsujin, the very same defensive weapon that covered all of Japan in the Rust Wind. It seems like no one can stop Kurokawa, and yet at the very moment Jabi feels that despair, a familiar face appears before Kurokawa...

Bisco falls into Tetsujin's reactor, taking Kurokawa down with him. The reactor begins to overload, with Milo and the others just barely escaping in time as the dome starts to collapse. However, they're given no time to grieve their loss of Bisco before their next trial assails them. With Bisco gone, Milo tries to figure out what he can do on his own now.