Just Cause is set on a fictional South American tropical island called "San Esperito", where the player works as CIA black ops agent Rico Rodriguez in a guerrilla war to overthrow San Esperito's dictator, who may be in possession of weapons of mass destruction.The game draws its premise (and name) from the real-life United States invasion of Panama, code-named "Operation Just Cause", which involved United States military action to overthrow military leader Manuel Noriega.

Rodriguez has been described by developers as being "the child of one thousand comic books and action movies. He is James Bond, Mad Max, Jason Bourne, El Mariachi, Wolverine, Punisher, Rambo, Tony Montana, Han Solo and Vincent Vega all rolled into one. With a touch of Enrique Iglesias to top it all off!"