Ghosts takes place in an alternate timeline, and centers on a conflict between the United States and The Federation, a coalition of southern American countries. The two factions have been at war for ten years, and entire cities have been destroyed. As with previous Call of Duty games, the player takes control of a number of characters from different points of view from the conflict, but the story is told largely from the point of view of a US 'Ghost' team, a special forces team specializing in the clandestine and the covert as they track down a former Ghost that has been captured and brainwashed by the Federation.

As with all titles in the series Call of Duty: Ghosts has a large multiplayer portion. Standard CoD modes such as free for all and Team deathmatch make an appearance, along with Ground War, which rotates between Domination and Team Deathmatch and Blitz, which is similar to capture the flag, but instead of having flags, players must get to portals located at the enemy spawn point in order to score.