A nomadic alien race known as the Cthulhu, a species composed entirely of females, targets Earth as their new home after losing their own world. To conquer the planet without destroying it, they deploy parasitic creatures called Vedims that infest and transform humans into monstrous forms. However, their invasion faces unexpected resistance from Iczer-One, a powerful android warrior originally created by the Cthulhu who has rebelled against them.

Iczer-One possesses a giant humanoid mecha called Iczer-Robo, but she cannot unlock its full power without a human synchronization partner whose intense emotions of loss and anger can activate its ultimate weapons. Her search leads her to Nagisa Kano, an ordinary Japanese schoolgirl. The moment Iczer-One makes contact with Nagisa, the Cthulhu target the girl for elimination, transforming her classmates and then her parents into parasitic Vedims before her eyes. Though Iczer-One destroys the creatures, Nagisa is left traumatized and horrified, blaming Iczer-One for the destruction of her family and refusing to cooperate.

Meanwhile, the Cthulhu leadership aboard their vessel, the Cthulhu Moon, launches a full military assault. The Cthulhu leader, Sir Violet, dispatches the warrior Cobalt in a giant mecha called Delos Theta to devastate Earth's cities and draw out Iczer-One. Forced into battle, Iczer-One teleports herself and Nagisa into the Iczer-Robo. The fight turns in their favor only when Nagisas consuming rage over her parents murder triggers the robot's hidden power, allowing her to personally destroy Delos Theta and kill Cobalt.

In response, the entity known as Big Gold, a mysterious golden, childlike mechanical life form that has corrupted the Cthulhu, creates Iczer-Two. This evil android, who calls herself Iczer-Ones sister, possesses her own mecha, Iczer-Sigma. Sir Violets true benevolent personality has been suppressed by Big Golds influence, transforming her into a puppet leader. Cobalts grieving lover, Sepia, volunteers to become Iczer-Twos synchronization partner, seeking revenge. As open warfare between the Cthulhu and Earths military reduces civilization to a post-apocalyptic wasteland, Nagisa discovers a young girl named Sayoko caring for her ill mother. Finding a purpose in protecting Sayoko, Nagisa finally chooses to fight alongside Iczer-One.

Iczer-Two and Sepia attack in Iczer-Sigma, defeating Iczer-One in the initial battle. During the rematch, Iczer-Two cruelly uses Iczer-Sigma to stomp on Sayoko, who has come to watch. Sepia is horrified by this act of pointless cruelty, breaking their synchronization, while Nagisas grief and fury once again empower Iczer-Robo to destroy Iczer-Sigma. Sepia chooses to die in the explosion, while Iczer-Two escapes. Sayoko survives thanks to a protective bracelet Iczer-One gave Nagisa.

In the final confrontation, Iczer-Two kidnaps Nagisa and subjects her to powerful mind control. Iczer-One fights her way through the Cthulhu fortress, but when she reaches Nagisa, it is too late. Following Nagisas telepathic instruction, Iczer-One kills her to prevent Earths conquest. Yet Nagisas spirit merges fully with Iczer-One in that moment, achieving true synchronization. Empowered, Iczer-One defeats Iczer-Two and confronts Big Gold.

Big Gold reveals that it and Iczer-One were created simultaneously by an ancient wish-granting machine. When the Cthulhu matriarch, despairing of ever finding a home, wished for salvation, Big Gold was born from that despair to grant her desire by transforming the Cthulhu into a conquering force. Iczer-One was born as the opposing principle of conscience, destined to destroy what Big Gold created. After absorbing Big Gold, Iczer-One uses their combined power to restore Earth to its original state, erasing the invasion from history. She revives Nagisa, who has no memory of the events, and bids her a final farewell before departing with the Cthulhu ship to find them a new homeworld.