The game sees the return of former Task Force 141 Cpt. John "Soap" MacTavish (voiced by Kevin McKidd), former S.A.S. Cpt. John Price (Billy Murray) and Russian informant "Nikolai", who are on the run after killing the rogue U.S. Army Lt. General Shepherd, the main antagonist of the previous game. However, for most of the game, the player will control Yuri (Brian Bloom), an ex-Spetsnaz who joins Price on his hunt for Russian Ultranationalist leader Vladimir Makarov (Roman Varshavsky). Makarov returns as the game's primary antagonist, and has a new contact named "Volk", a Russian bombmaker in Paris, France. Several new playable characters have been added, including: Delta Force operative Sgt. Derek "Frost" Westbrook; S.A.S. Sgt. Marcus Burns; and Andrei Harkov, a Russian federal security agent tasked with protecting the Russian President. Just like President Al-Fulani in the first game, Soap is only "playable" during the game's opening sequence; while Price becomes the player character in the game's final mission, Dust to Dust. The player also takes brief control of a civilian tourist in London, seconds before he and his family are killed by a chemical agent; as well as an AC-130 TV Operator during Team Metal's escape from Paris in the mission Iron Lady.
The player assumes the role of various characters during the single player campaign, changing perspectives throughout the progression of the story, which, like its predecessors, is divided into three sets of missions called "Acts". Each mission in an act featuring a series of objectives that are displayed on the heads up display, which marks the direction and distance between such objectives and the player. Damage to the player is shown by the visualization of blood-spatter or red-outs on the screen. The player's health regenerates over time as long as the player character refrains from taking damage for a limited time. Mission objectives vary in their requirements, ranging from having the player arrive at a particular checkpoint, to eliminating enemies in a specified location, to standing their ground against enemy squadrons, directing remote-operated weapons, and planting explosive charges on enemy installations. The player is also accompanied by fellow soldiers who cannot be issued orders. Like its predecessor, the game includes an interactive scene of a terror attack against civilians, which the player is given the option of skipping due to the portrayal of graphic and potentially upsetting content, including harm to children.