In a post-apocalyptic future, after a virus has wiped out ninety-nine percent of the Earth's population in the year 2011, survivors inhabit Bregna, a walled city-state, which is ruled by a congress of scientists. Æon Flux is an assassin-member of the 'Monicans', an underground rebel organization who communicate telepathically through use of pills and are led by The Handler. After a mission in destroying a surveillance station, Æon comes home to find her sister Una killed, supposedly mistaken for a Monican. When Æon is sent on a mission to kill the government's leader, Trevor Goodchild (Marton Csokas), she discovers that she is unwittingly playing a part in a secret coup.


This discovery brings into question the origin and destiny of everyone in Bregna; and in particular, Æon's personal connection to the man she has been sent to assassinate. Ultimately she learns that she is a clone of Goodchild's late wife Katherine, and that he is in fact trying to save humanity by secretly creating a cure for the infertility caused by the antidote for the disease which killed ninety-nine percent of the Earth's population. It turns out that all newborn children in Bregna are clones created with recycled DNA, with the dead constantly being reborn into new individuals and still bearing parts of the memories of their ancestors. One of Trevor's experiments is successful but Oren Goodchild (Jonny Lee Miller), Trevor's brother, destroys the research in an attempt to stay in power and live forever in the form of clones of himself.


However, in a confrontation with Trevor and Æon, Oren reveals that humanity itself has adapted and some people have regained the ability to have babies on their own. Æon is ultimately forced to go up against both her former allies and Oren but she manages to convince the Monicans not to listen to The Handler and take her side to kill Oren and his men. In a final act, Æon prepares to destroy the housing facility where the DNA used for cloning is stored, a dirigible constantly floating in the sky. She meets the old man who monitors the DNA, who was the doctor who preserved her DNA when Oren ordered it to be destroyed all those years ago. The subsequent crash breaks the wall surrounding the city and for the first time in centuries the population is able to expand into the outside world.