The first season of FLCL is a coming-of-age story and revolves around Naota Nandaba, a 12-year-old, working-class boy living with his widowed father and grandfather. His life in the city of Mabase is interrupted by the arrival of a Vespa-riding maniac named Haruko Haruhara. She runs over Naota then revives him with CPR before hitting him on the head with her left-handed, electric bass guitar (a blue, vintage Rickenbacker 4001) and proceeds to stalk him. Finding Haruko weaseling her way into his life as a live-in maid, Naota discovers that the head injury she caused created an "N.O." portal, which giant robots produced by a company known as Medical Mechanica emerge from periodically. The first of these robots is hit on the head by Haruko and becomes a friendly service robot later named Canti. Canti ingests Naota to assume the reddened form he first had when fighting the robots sent after him.
Haruko claims she is an alien investigator from the Galactic Space Police Brotherhood, and her presence places Naota and those around him in danger. The Interstellar Immigration Bureau's Commander Amarao, who Haruko has a history with, instead reveals she is an apathetic seductress seeking a space-manipulating being called Atomsk who was partially contained within Canti. Every time Naota is absorbed by Canti, Atomsk is gradually brought to Earth. As Atomsk is held in Medical Mechanica's custody and Haruko ultimately places Earth under threat, the company eventually turns their factory stationed on the planet into a doomsday terraforming device, attempting to have Naota and Canti absorbed by the doomsday device's Terminal Core. Haruko's plan fails as Naota ends up becoming Atomsk's host and then releases him into the universe after a brief battle that ends Medical Mechanica's attack on Earth. Haruko follows after Atomsk, and Mabase returns to some normalcy.
In the second season, FLCL Progressive, Haruko returns to Mabase years later after a failed attempt to contain Atomsk, although she did manage to absorb him. Placing herself as a middle school homeroom teacher, Haruko targets a 14-year-old girl named Hidomi Hibajiri through her classmate and eventual love interest Ko Ide. Haruko finds opposition in both the headphones Hidomi wears and Julia Jinyu, a more stoic offshoot of Haruko that splintered from her during her initial attempt to control Atomsk's power. Haruko eventually eats Julia to restore herself, and uses Ide to get to Hidomi. Like before, this causes conflict between Medical Mechanica and the Interstellar Immigration Bureau, as the latter was reverse-engineering Canti's technology to utilize the N.O. Channel's energies for their own use. Atomsk appears on Earth as planned, but Haruko ends up failing again with a freed Julia taking her leave. Haruko regains her composure and resumes her hunt for Atomsk as Hidomi and Ide begin their relationship while Mabase rebuilds after much of it was destroyed by Medical Mechanica.
In the final season, FLCL Alternative, Haruko enters the life of high school student Kana Koumoto and her friends as she became a mentor of sorts to Kana in helping the teen's transition into adulthood as Medical Mechanica begins its assault on Earth.