"Cowboys & Aliens" derives from a graphic novel written by Fred Van Lente and Andrew Foley from an original idea by Rosenberg. The story centers on an Old West battle between the Apache and Western settlers, including a former Union Army gunslinger named Zeke Jackson (Downey), that is interrupted by a spaceship crashing into the prairie near Silver City, Ariz.

The story draws a parallel between the American imperialist drive to conquer the "savage" Indians with its advanced technology and the aliens' assault on Earthlings, who must join together to survive the invaders' attack.