Established in 2032, Mega-City One was conceived as an answer to the massive overcrowding plaguing the cities of North America. Originally designed to house 350 million citizens, the population of Mega-City One soon swelled to an astounding 800 million people, a number that would remain constant until the city was devastated by the effects of the Atomic Wars - the Great Atom War of 2070 and later the Apocalypse War of 2104, which reduced its population to 400 million people with living space for half that number. Due to a number of other disasters and crises that have affected the city, and immigration to Mega-City One, the population remained stable until 2134. Following the Day of Chaos, the city has been reduced to a devastated minor state.

In the early 22nd century, it stretched roughly from southern Maine down through Florida, far into Ohio and/or West Virginia to the west, and to the Quebec City-Windsor Corridor in Canada in its north west. From 2104 onwards, it had been scaled back to roughly New Hampshire through North Carolina.