The game takes place in the year 2014, one day after the events of Ghost Recon: Advanced Warfighter, just south of the United States border and deals with the conflict between a Mexican rebel group, Mexican Loyalists, and the United States Army for a time span of 72 hours. A wide array of location types featuring mountains, small towns, urban environments, and a large hydro-electric dam just north of the US-Mexico border.

The game begins in Ciudad Juárez just after General Ontiveros‘ rebellion, where Mexican rebel activity has caused civil unrest throughout Mexico. Despite the death of Carlos Ontiveros, the insurgency has continued under the leadership of Juan de la Barrera, even spreading into other Latin American states, including Colombia, Honduras and Panama where rebel forces have effectively shut down the Panama Canal. The Ghosts are sent to Mexico by General Joshua Keating to investigate claims that the rebels are in possession of a dirty bomb, as well as prevent the rebellion from directly assaulting US soil. Immediately after arriving in Mexico, the Ghosts are put to work destroying a sizable rebel position guarded by two large artillery pieces, enabling additional American forces to reach the main battle-zone. Shortly thereafter, Captain Scott Mitchell aids an aerial attack against a rebel supply base from Black Hawk 5, annihilating two enemy weapons convoys in the process. The Ghosts also learn that de la Barrera has obtained old Ukrainian Red Star IV nuclear warheads. Combined with several medium-range, Pakistani-built Kashmira-II missiles stolen from cargo ships in the Canal, the rebels now possess the ability to destroy any major city in the United States.