The game's main protagonists are the Ghosts, a force of U.S. Special Operations personnel trained to conduct clandestine missions behind enemy lines. The unit is led by retired U.S. Army Captain Elias Walker . He is joined by his sons Logan and David "Hesh" Walker , along with Booth and Neptune, a trained German Shepherd named Riley, and Cdr. Thomas A. Merrick of the Navy SEALs.

Call of Duty: Ghosts is set in an alternate timeline that follows the nuclear destruction of the Middle East. The oil-producing nations of South Americaform the Federation in response to the ensuing global economic crisis and quickly grow into a global superpower, swiftly invading and conqueringCentral America and the Caribbean. The game's main antagonist is Gabriel Rorke, a former Ghost who turned traitor after being captured and brainwashed using torture and hallucinogens who now works for the Federation.