Earth is attacked by an alien race, known as the Cthulhu (クトゥルフ kutourufu?). According to their initial strategy, the Cthulhu use parasitic creatures, called vedims (ヴェデム vedemu?), to infest and replace humans across the world. Their hope is to eradicate humanity and take the world without damaging it in an open war. However, Iczer-1 appears and begins rooting out and destroying the vedims. Upon learning this, the Cthulhu plan to initiate a full military invasion of Earth.
Iczer-1 searches for her "synchronization partner," a human whose sense of loss and anger at the destruction wrought by the aliens will allow her to co-pilot Iczer-1's mecha, the Iczer-Robo (イクサーロボ Ikusā Robo?), and unleash its full weapon capabilities. Ultimately she chooses Nagisa Kanō, a Japanese schoolgirl, as her partner. No sooner than she makes contact with her, than the Cthulhu agents begin trying to assassinate her, first at her school, by transforming her classmates into vedims, and later by transforming her parents into another type of parasitic creature, the Delvittse (ディルウェッツェ Diruvettsue?).
Simultaneously, the Cthulhu pilot, Cobalt, prepares to lead their champion unit, a giant mecha called Delos Theta, against the human military with the ultimate objective of flushing out Iczer-One and destroying her before she can unite with her partner. First the aliens transport in their battle station, a giant black marble pyramid, which appears above the skyline of Tokyo, causing widespread devastation. Then Cobalt launches and begins to destroy the city and all military forces in the area. Iczer-One senses the disturbance and teleports Nagisa and herself into her "other self", the Iczer-Robo, to confront Delos Theta. Initially, the battle fares poorly for Iczer-1, but eventually Nagisa's rage over her parents' murder consumes her, and she triggers, unleashing a huge energy beam that cripples the enemy robot. Nagisa then delivers the final blow herself, killing Cobalt in the process.
The Cthulhu leader, Sir Violet, responds by developing her own version of Iczer-1, the burgundy-haired Iczer-2, and using the traumatized lover of Cobalt, Sepia, as her partner. In the following days, warfare between activated vedim and human forces, lay waste to most of Earth's civilization, turning the world into a post-apocalyptic wasteland. Nagisa discovers a young girl named Sayoko in the ruins of Japan, tending her unconscious mother. She takes the family into her home, but the mother turns into a vedim, and numerous others begin to teleport into the house. Nagisa uses a bracelet given to her by Iczer-One and is able to protect Sayoko and herself within a force field.
Iczer-1 fights Iczer-2 in a massive battle over the ruins of Japan and is defeated, but escapes to regroup with Nagisa and rescue her. Iczer-2 and Sepia arrive in their giant robot, Iczer-Sigma. Iczer-Robo appears, and Nagisa leaves Sayoko with her bracelet before going with Iczer-1 to fight. Again the battle goes poorly for Iczer-Robo until, in a fit of sadism, Iczer-2 stomps on Sayoko, who has come to watch. Immediately Sepia's morale is broken and Nagisa once again triggers the beam weapon of Iczer-Robo, destroying Iczer Sigma. Iczer-2 barely manages to teleport away before the robot explodes. Sepia chooses not to escape, wanting to be reunited with Cobalt.
Iczer-1 is still badly injured from her fight with Iczer-2, and the two relax in a country meadow to recover. Sayoko is shown to be alive, thanks to Nagisa's bracelet. Iczer-2 retreats to a shadow realm to brood over her defeat before returning with two elite armored vedims, Reddas and Blueba, and abducts Nagisa. Iczer-1 must then single-handedly assault the Cthulhu fortress to get Nagisa back and kill Big Gold. Meanwhile, Iczer-2 tries to get Nagisa to willingly join her, threatening to otherwise force her. By the time Iczer-1 has reached the chamber where Nagisa is being kept, it is already too late. She has been placed under powerful mind control by Iczer-2, and Iczer-1 is forced to kill her. In dying, however, Nagisa's spirit merges with Iczer-1 and for the first time they fully synchronize. Iczer-1, fueled by Nagisa's sacrifice, defeats Iczer-2 and has her final confrontation with Big Gold. She later fights and kills Iczer-2, who reveals she just wanted a partner like Nagisa.
Big Gold relates that he and Iczer-1 were both created at the same moment, by an ancient alien machine built to grant the desires of its creators. The Matriarch of the Cthulhu, who would eventually become Sir Violet, had passed within range of the machine just as she exclaimed in despair that her race would die in space and never find a new home. At that moment, Big Gold had appeared to tell her that her wish was granted. He had changed her idyllic society into a fascist nightmare, and had mutated the once benign vedim into their current parasitic forms. Big Gold was an embodiment of "Desire" and it had remade the Cthulhu race. Iczer-1 was the other half of this prophecy. She was "Conscience" and her role was to fulfill the Cthulhu matriarch's wish and destroy them all on the eve of finding a new homeworld.
Iczer-1 destroys him. In a final act, using the power of their synchronization and tapping into the ancient wish-granting machine, Iczer-1 is able to restore Earth to the way it was before the Cthulhu attack. The Cthulhu fade even from memory and Nagisa is left in the moment where she first appeared in the movie, daydreaming and late for school. She catches a brief glimpse of Iczer-1, but does not know who she is.
