"The Big O" is set in Paradigm City, a metropolis where the inhabitants have lost their memories due to a mysterious event known as "The Event" 40 years prior. The city is controlled by powerful corporations, and its society is divided between the wealthy elite and the impoverished masses. The protagonist, Roger Smith, is a professional negotiator who resolves conflicts and retrieves stolen property for clients. He operates under the guise of a suave, noir-inspired detective, often accompanied by his android companion, R. Dorothy Wayneright, and his loyal butler, Norman Burg.

Roger’s life takes a dramatic turn when he encounters a massive, ancient robot known as a "Megadeus," specifically the titular Big O. This mecha, buried beneath the city, awakens in response to a crisis, and Roger becomes its pilot. The Big O serves as both a weapon and a symbol of power, capable of combating other Megadeuses that emerge throughout the series. These battles often tie into the larger mystery of Paradigm City’s forgotten past and the true nature of "The Event."

As the story progresses, Roger uncovers fragments of the city’s history, including the existence of other Megadeuses and their pilots. He crosses paths with Angel, a mysterious woman with ties to the city’s corporate elite, who seems to know more about the past than she reveals. The narrative explores themes of memory, identity, and control, as Roger and his allies piece together the truth behind Paradigm City’s amnesia and the role of the Megadeuses in shaping its future.

The series blends elements of mecha action, noir storytelling, and psychological intrigue, with a focus on the moral ambiguities of power and the consequences of forgotten history. The characters’ motivations are often shrouded in mystery, reflecting the fragmented nature of their world. Roger’s journey is as much about uncovering the truth of Paradigm City as it is about confronting his own place within its fractured society. The interplay between the personal and the political drives the narrative, culminating in a climactic confrontation that challenges the very foundations of the city’s existence.