Pushed to the brink of extinction in a post apocalyptic world, humanity is under constant threat from giant creatures known as klaxosaurs, which are sub-divided into at least four categories based on their size: "Conrad", "Mohorovičić", "Gutenberg" and "(Super) Lehmann". Pushed to the brink of annihilation, parasites are raised to pilot giant mecha known as Franxx in boy-girl pairs. A male parasite is termed a "stamen" and a female parasite is referred to as a "pistil" (the male and female reproductive parts of a flower, respectively). Parasites are artificially-created and have short lifespans.

A team of ten parasites is assigned to the experimental Squad 13 of Plantation 13. One of them, Hiro (Code:016), is a former pilot-candidate prodigy who can no longer synchronize with his partner and they both fail to complete the training program. While skipping his squad's graduation ceremony, Hiro encounters Zero Two (Code:002), an elite Franxx pilot with klaxosaur blood, red horns, and an infamous reputation as the "Partner Killer". It is rumored that Zero Two's partners are killed after pairing with her by the third time. Shortly after, a Klaxosaur attacks, disrupting Hiro's graduation ceremony and leaving Zero Two's partner killed in action. Despite the rumors, Hiro volunteers to become her new partner, or as Zero Two calls him, her "darling".