The series takes place in an alternate history 1950s, in which an alien civilization known as the Chimera have invaded and conquered Earth, expanding their armies by capturing humans and transforming them into monster-like super soldiers to fight for them.

The game follows the story of Tom Riley, a firefighter who sets out to find his family while fighting the Chimera, who have now taken over the American east coast.

[9] In August 2018, Insomniac's community director James Stevenson called chances of a Resistance 4 "a longshot" revealing that neither the developer, nor Sony who owns the IP, were talking about a sequel.

[12] The alternate history of the Resistance series diverges from current history primarily at the end of World War I, leading to the formation of the European Trade Organization, a continental peacekeeping alliance, and worldwide peace, preventing the Great Depression, the rise of the Nazi Germany, and World War II, but also leading to Franklin Delano Roosevelt losing the 1940 presidential election to Montana Senator Noah Grace who leads the U.S into a semi-totalitarian isolationist state, as well as the rise of an isolationist Russian Empire, as before his abdication, Nicholas II appointed his youngest brother Grand Duke Mikhail as Tsar, who crushed the Russian Revolution.

In 1921, Russia initiated a communications blackout with the rest of the world and built a wall against its European border called the "Red Curtain."

Word spreads of small towns, villages, and eventually cities in Russia and Eastern Europe that are destroyed within a single night.

European intelligence agencies attempt to listen in on Russian radio stations, only to hear a single message repeated over and over: "Brotherhood, Strength, and Fortitude ... in the face of the angry night".

Sometime after the invasion of England, the SRPA (Special Research Projects Administration) begins experimenting with the virus, supposedly to find a cure.

It details what happened to Nathan Hale during the two years between the events that unfolded in Iceland, after his extraction from Great Britain, and later in San Francisco and where the Chimera launch the invasion of the United States.

The first issue, "Resistance #0" (which was available as part of the Resistance 2 Collector's Edition), details the early history of Private Jordan Adam Shepherd, the seemingly innocent soldier who volunteered to be a test subject in Project Abraham, and, due to the machinations of Doctor Fyodor Malikov, would transform into "Daedalus", the Leader of the Chimera.

Another comic issue released was called "Metastasis", telling the tale of a Nathan Hale mission and how he is to retrieve an antidote to the chimera virus.