A secret pharmaceutical project known as the Amazon Project, conducted by the Nozama Pharmacy company, aimed to create artificial lifeforms using experimental Amazon Cells. Two years before the series begins, an accident at the research facility releases approximately 4,000 of these experimental subjects, known as Amazons, into the general population of a modern Japanese city. These creatures can appear human but are driven by an overwhelming, feral hunger for human flesh. In response, Nozama Pharma secretly operates the Nozama Peston Service, a specialized extermination team that hunts down the rogue Amazons to prevent public panic.

The story centers on two men who become the most formidable hunters of their own kind. Haruka Mizusawa is a meek young man who has been raised in isolation and becomes Kamen Rider Amazon Omega using the Amazons Driver. He is a unique type of Amazon, created by having human genes transplanted into Amazon Cells, and he struggles to suppress his predatory instincts while asserting his humanity. In contrast, Jin Takayama is a former cell biologist who worked on the Amazon Project. Horrified by his creation, he injects himself with the cells to become Kamen Rider Amazon Alpha. Jin is a feral, wandering warrior driven by a simple and brutal creed: to exterminate every last Amazon, including himself eventually, in order to protect humanity. Their paths cross when Haruka, seeking to understand his origins, reluctantly joins forces with the Peston Service extermination team, which includes the capable leader Makoto Shido and his comrades.

The first season explores the conflict between these two contrasting Riders. Haruka represents the tame or cultured Amazon, trying to find a balance and protect those he cares about, such as his adoptive sister Mizuki Mizusawa. Jin represents the wild Amazon, acting on pure instinct and viewing any Amazon, regardless of their moral compass, as a threat to be eliminated. As the Amazon threat escalates, the government becomes involved, and a massive extermination operation codenamed Tlaloc is launched, using a specialized gas to wipe out the creatures en masse. This culminates in a crisis known as the Awakening, forcing both Haruka and Jin to confront their own natures and the true extent of the project's horrors.

The second season takes place five years later in 2021. While society has seemingly recovered, a new, more insidious threat emerges: a mutated variant of the Amazon cells, called lysogenic cells, spreads like a virus, spontaneously transforming ordinary humans into Amazons. A new government organization called 4C (Competitive Creatures Control Center) is formed to secretly eliminate infected individuals. The narrative shifts focus to a new protagonist, Chihiro, who transforms into Kamen Rider Amazon Neo. Chihiro is the biological son of Jin Takayama and has been raised as an Amazon, constantly battling his cannibalistic urges. He encounters Iyu, a mysterious girl who is a Crow Amazon, an emotionless biological weapon resurrected as part of a secret Sigma Project.

As Chihiro fights to retain his humanity and finds himself drawn to Iyu, the original characters return from hiding. Haruka re-emerges from isolation with an upgraded form, Amazon New Omega, to help the younger Amazon. Jin Takayama also returns, now partially blind but more relentless than ever, continuing his personal crusade to destroy all Amazons, even his own son. The season delves into themes of survival, the cycle of violence, and whether a being designed to eat humans can ever find redemption. The conflict involves corporate remnants of Nozama Pharma and the brutal methods of 4C, leading to a tragic and violent confrontation that questions if there can ever be a final judgment for the Amazons. The storyline concludes with the theatrical film The Last Judgement, which brings the narratives of Haruka and Jin to a definitive end.