Early in the first episode (after the characters and the bland town of Mabase have been introduced by a monologue from Naota) events kick off when a strange and mischievous girl named Haruhara Haruko arrives suddenly in town and runs Naota over with her Vespa and then, for no obvious reason, hits him on the head with her Rickenbacker bass guitar. Soon afterwards, Naota discovers that being hit with Haruko's bass left more than just a bump - it created a large horn that is actually an early manifestation of a robot. By hitting him in the head, Haruko activated Naota's latent N.O. portal, which allows him to pass physical objects from one astronomically distant point to another by way of his head. This is not immediately obvious, however.

Later that day Naota finds Haruko in his house, hired by his father as a live-in maid. It is gradually revealed that Haruko is in a confrontation with a company named Medical Mechanica (the name is debated to be Medical Meccanica as shown in one episode) (whose iron-shaped factory building dominates the Mabase skyline) about recovering a powerful being named "Atomsk".

In addition to being hounded by Haruko, who uses the portal she opened in his head for her own selfish purposes, Naota must also face (and occasionally grapple with) the other characters of FLCL. He is being watched by a man named Commander Amarao. As the series progresses, an ideological tug of war emerges between Amarao and Haruko for Naota, whose powers Haruko needs to regain Atomsk. Amarao (whose beliefs are suspect for accuracy) views Atomsk (incorrectly) as a humanoid Haruko is in love with, and believes Medical Mechanica to be bent on a goal of interplanetary conquest. Amarao and his assistant, Lt. Kitsurubami, are monitoring Haruko and Medical Mechanica for intergalactic legal reasons and are attempting to save the Earth as the conflict between Haruko and Medical Mechanica escalates