A secret experiment by the pharmaceutical giant Nozama Pharmaceuticals has given rise to the Amazons, artificial life forms created from Amazon cells that possess a powerful instinct to devour human protein. Two years before the story begins, an accident at a research facility released 4,000 of these experimental creatures into society. Disguised as ordinary people, they live among the human population until the drug in their control armlets wears off after approximately two years, at which point they awaken, their hunger takes over, and they become man-eating monsters.

To contain the threat, Nozama Pharmaceuticals secretly operates the Nozama Pest Control Service, a mercenary extermination squad led by the pragmatic Makoto Shido and including members such as the skilled Nozomi Takai, Kazuya Misaki, and Kota Fukuda. Their mission is to hunt and eliminate Amazons before the public becomes aware of their existence.

The story centers on two very different men who become Kamen Riders. Jin Takayama, a former developer of the Amazon project, carries immense guilt over the disaster he helped create. He voluntarily injected himself with Amazon cells and uses the Amazons Driver belt to transform into the feral, red-eyed Kamen Rider Amazon Alpha. His mission is absolute: he will hunt down and kill every single Amazon, including himself when his task is complete. He lives with his partner Nanaha Izumi, who supports his grim crusade.

The second Rider is Haruka Mizusawa, a sheltered young man raised by Reika Mizusawa, a high-ranking Nozama executive. Believed to have a weak constitution, Haruka spends his days confined to his home, visited only by his adoptive sister Mizuki. When he stops taking his medication, his true nature awakens: he is an Amazon himself. After transforming into a green, insect-like creature, he encounters Jin, who gives him a spare control armlet and later a spare Amazons Driver, allowing him to become Kamen Rider Amazon Omega. Unlike Jin, Haruka begins with no clear purpose, torn between his human upbringing and his monstrous instincts.

As Haruka joins the Pest Control Service to find his place, he and Jin form an uneasy alliance. Jin sees all Amazons as threats to be eliminated and views Haruka as an enemy he will eventually have to kill. Haruka, however, struggles to see himself and other Amazons who resist their cannibalistic urges as mere monsters. This philosophical divide deepens as the season progresses, with Haruka advocating for the possibility of coexistence while Jin remains committed to total extermination.

A major narrative arc involves Mamoru, a gentle Amazon who refuses to eat humans and works at a recycling plant. Haruka befriends him and tries to protect him from extermination, forcing Jin to confront the question of whether an Amazon that does not kill deserves to die. Another arc introduces Jun Maehara, a former member of the Pest Control Service who was killed by an Amazon and resurrected as the mindless, powerful Kamen Rider Amazon Sigma, becoming a threat to both humans and Amazons alike.

The season builds toward Operation Tlaloc, a plan by Nozama Pharmaceuticals to deploy drones that release a lethal anti-Amazon gas across the city, killing every Amazon regardless of their threat level. As the gas spreads, the Pest Control Service team fractures. Haruka rushes to save Mamoru and other peaceful Amazons, while Jin accelerates his killing spree to destroy as many as possible before the gas does. The two Riders clash in a final confrontation, not as allies but as ideological enemies. Haruka chooses to embrace his Amazon identity and fight for the survival of those like him, while Jin remains resolute in his vow to end the Amazon species. The season ends ambiguously, with both Riders surviving their battle, the fate of the surviving Amazons uncertain, and the cycle of hunting and being hunted poised to continue.