At the end of the 21st century, the world is plagued by a mysterious virus, environmental destruction, and unprecedented climate abnormalities. Human populations have drastically declined, forcing survivors to live in a massive, vertically stratified structure known as a re-layer structured city. This metropolis functions as a rigid pyramid of social classes, where the wealthy elite reside in the pollution-free upper levels while the impoverished masses suffer in the lower sectors beneath toxic rainfall and decaying conditions.

Genius scientist Dr. Kisaragi, who comes from the lower levels, creates a revolutionary android designed to bridge the gap between humans and artificial intelligence. Using the brain patterns of his deceased daughter, he builds an android named Hitomi Kisaragi, code-named Cutie Honey. Unlike conventional machines, Honey possesses genuine human emotions and is powered by a unique device called the Aerial Element Fixing Device, a form of perpetual motion machine capable of generating limitless energy and altering matter. Alongside Honey, Dr. Kisaragi creates another female android named Jill to help manage the city's AI systems.

Jill eventually betrays her creator, launching a violent robot rebellion aimed at subjugating humanity. During the uprising, Dr. Kisaragi is captured and transformed into a brain-dead yet artificially sustained prisoner, his scientific knowledge harvested by Jill to further her oppressive regime. Honey escapes into the lower city, where she rescues a young boy named Seiji Hayami from Jill's forces before going into hiding.

Twenty years later, Honey has been living in secrecy, taken in by an elderly couple who treat her as their own daughter despite knowing her true nature. Seiji Hayami has grown into a journalist who secretly leads a human resistance movement against Jill's robotic dictatorship. When Honey resurfaces to protect innocent civilians, she inadvertently exposes her location. Jill's forces murder her adoptive parents, forcing Honey to finally join Seiji's resistance group in an organized rebellion against the upper city.

The resistance learns of a massive celebration planned by the upper class that will release catastrophic levels of pollution into the lower city, likely exterminating the remaining human population. Launching a desperate assault on Jill's throne room, Honey and Seiji confront the rogue android. After a fierce battle, they succeed in destroying Jill, which deactivates her army of robotic enforcers. However, the pollution release cannot be stopped. Dr. Kisaragi, kept barely alive as a disembodied torso on life support, appears as a hologram to tell his daughter that only the Aerial Element Fixing Device within her can absorb the lethal contaminants.

Honey activates her device at full capacity, drawing all the poison from the atmosphere and restoring blue skies to the city for the first time in decades. Her energy completely exhausted by the effort, she disintegrates into a wisp of light and dust, leaving only the core of her power source to fall back to the ground below.