The year is 2016, and despite the efforts of the United States Marine Corps and the Special Air Service, the Ultranationalists seize control of Russia and declare Imran Zakhaev a hero and martyr, erecting a statue of him in the heart of the Red Square. Meanwhile, Vladimir Makarov, one of Zakhaev's former lieutenants, begins a campaign against Europe by committing brutal acts of terrorism over the course of five years. In Afghanistan, U.S. Army Ranger PFC Joseph Allen assists in the taking of a city from a local militia. Impressed by Allen's abilities, Lieutenant General Shepherd recruits him into "Task Force 141", an elite, multi-national counter-terrorist unit under Shepherd's command. Meanwhile, two other members of 141, Cpt. 'Soap' MacTavish and Sgt. Gary 'Roach' Sanderson infiltrate a Russian airbase in the Tian Shan mountains to retrieve an ACS (Attack Characterization System) module from a downed satellite.
Allen is later sent on an undercover mission in Russia for the CIA, joining Makarov in a massacre of civilians at the Zakhaev International Airport in Moscow. Makarov has been aware of Allen's identity and kills him during extraction, leaving his body to spark a war between Russia and the United States of America. Angered by what was believed to be an American-supported terrorist attack, Russia retaliates with a massive surprise invasion on the United States after bypassing its early warning system, revealing that the ACS module MacTavish and Sanderson recovered had already been compromised before its retrieval. Sergeant Foley leads his squad of Army Rangers, including Pvt. James Ramirez, in defense of a suburb in north-eastern Virginia against the Russian invasion. They then proceed towards a war-torn Washington, D.C., where U.S. forces are fighting the Russians for control of the capital city.
Meanwhile, 141 searches for evidence that implicates Makarov as the mastermind behind the airport massacre, as all proof of Makarov's involvement died with Allen. Intelligence leads them to a Favela in Rio de Janeiro, where the team investigates leads on Makarov's contact, weapons dealer Alejandro Rojas. They find out from Rojas that Makarov's worst enemy, known as Prisoner #627, is locked up in a Russian gulag. The Task Force assaults the prison and manages to free 627, who is revealed to be Captain Price. Price agrees to aid Soap and Shepherd in tracking down Makarov, but decides that ending the war in America is their first priority. To end it, he temporarily goes rogue, and leads the 141 on a raid of a Russian port, where they gain control of a nuclear submarine. Price uses the submarine to launch a ballistic missile towards Washington D.C. He sets the warhead to detonate in the upper atmosphere, which unintentionally destroys the International Space Station and creates an electromagnetic pulse, which cripples vehicles and electronic equipment on both sides, giving the Americans a slight advantage. Back on the ground, Ramirez and his fellow squad mates seek shelter from the disabled aircraft that are now literally falling from the sky, and proceed to the White House. There, they receive a transmission informing them that the Air Force is preparing to carpet bomb the entire city to deny the Russians a strong foothold. Foley's squad fight their way to the White House and set off flares in the nick of time, aborting the air strike. Flares are lit on the rooftops of other landmarks, signifying that the city is still in American hands.
Narrowing down Makarov's hiding place to two separate locations, Task Force 141 decides to split up. Price and Soap travel to an aircraft bone-yard in Afghanistan, while Roach and Ghost raid Makarov's safe house on the Georgian-Russian border. At the safe house, Roach and his team obtain vital intelligence from Makarov's computer and escape with Makarov's men in pursuit. However, when they reach the extraction point Shepherd betrays them, retrieving the intelligence and taking it with him, murdering and leaving Roach and Ghost to burn in the process. Price and MacTavish quickly learn of Shepherd's betrayal, though Price states that he wasn't betrayed since he never trusted Shepherd. The duo then manage to escape an already ongoing battle between Shepherd and Makarov's men with Nikolai's help. After contacting Makarov and offering to kill Shepherd for him, Makarov grudgingly reveals Shepherd's location at a mountain base in Afghanistan, codenamed Site Hotel Bravo. Price and MacTavish raid the base in an attempt to take revenge on Shepherd in a suicide mission. During the infiltration, Shepherd tries to escape on a Zodiac motorboat, and a long boat pursuit ensues.
At the climax of the pursuit, Shepherd boards a Pave Low, only for Price to disable it by shooting the helicopter's rotor, causing a crash landing. Price and Soap tumble over a waterfall in the process. After recovering from the fall, a dazed Soap gets up and approaches the crashed Pave Low with only his knife. He sees Shepherd and moves in for the kill. Shepherd counters by slaming Soap onto a destroyed car and stabs him in the chest. Price tackles Shepherd and the two fight. Shepherd gets the upper hand, but Soap is able to pull the knife from his chest and throw it at Shepherd's eye, killing him.
Price regains consciousness and inspects Soap's wounds as Nikolai arrives in a helicopter to extract them. Nikolai warns them that they will be pursued, but Price insists that Soap receives medical attention. Nikolai mentions that he knows a safe place to go to ("Da, I know a place"), and Soap and Price, now globally wanted criminals, go into hiding.
