In a distant future where humanity has been driven to the brink of extinction by gigantic creatures known as Klaxosaurs, the remaining population lives in mobile fortress cities called Plantations. Children are raised in isolation within these cities, knowing nothing of the outside world or natural love, and are trained for the sole purpose of piloting giant mecha known as FranXX in boy-girl pairs to defend their race.

The story centers on Hiro, once a prodigy pilot who has lost his confidence and ability to synchronize with a partner, rendering him useless. On the day of his squad's graduation ceremony, Hiro wanders away and encounters a mysterious horned girl with a reputation as the Partner Killer, Zero Two. When a Klaxosaur attacks the Plantation, Zero Twos partner is killed, and she invites Hiro to pilot her FranXX, Strelizia, with her. Together, they achieve a powerful synchronization and easily defeat the creature. Zero Two, a human-Klaxosaur hybrid, begins calling Hiro her darling, and he becomes her new partner.

Hiro joins Squad 13, a team of young Parasites living in the birdcage of Plantation 13, including the assertive leader Ichigo, her caring partner Goro, the hot-headed Zorome, the gentle Kokoro, the quiet Mitsuru, and others. As the squad undertakes dangerous missions against increasingly powerful Klaxosaurs, they begin to question their rigid society, develop emotions like jealousy and love, and learn forbidden truths about the world. The manga diverges significantly from the original anime storyline starting from around volume four. Hiro and Zero Twos deepening bond challenges the authority of APE, the organization governing humanity, and its mysterious leader, Papa.

The narrative reveals that the Klaxosaurs are ancient beings defending the planet from a greater existential threat: VIRM, a malevolent alien intelligence. Zero Two struggles with her hybrid identity and her desire to become fully human for Hiro's sake. In the manga's climactic arc, Hiro and Zero Two merge completely with Strelizia to confront the VIRM forces. The story concludes on a more hopeful and definitive note than the anime. After defeating VIRM, the pair returns to Earth, having survived and retained their humanity. The final chapters show a rejuvenated planet and offer a glimpse of the grown members of Squad 13 living peaceful, fulfilling lives, having built a new world where children can be born naturally and experience freedom and love.