The game begins with Sergeant "Soap" MacTavish, Captain Price, "Gaz," and a small group of other SAS members infiltrating a cargo ship with Estonian registration numbers in the Bering Sea. After eliminating the crew and confirming the presence of a nuclear device onboard, the vessel comes under attack from hostile MiGs. The team manages to evacuate the sinking ship with the cargo manifest, which provides evidence of ties between a Russian ultranationalists group and a rebel faction in the Middle East.

Meanwhile, Russian ultranationalist Imran Zakhaev is set on returning his homeland to the times of the Soviet Union by revolting against the government and seizing a nuclear weapons stockpile. In order to draw international attention away from his plans in Russia, Zakhaev funds a coup d'état in an unnamed Middle Eastern oil-producing nation, organized by local rebel leader named Khaled Al-Asad. It begins with the televised execution of President Yasir Al-Fulani. The British and American governments discover the plot while monitoring Zakhaev's recent activities, and initiate a police action to stop the uprisings in both regions. After President Al-Fulani is executed, SAS is deployed to rescue their informant within the Russian ultranationalist group who has been compromised and held in ultranationalist territory in the Caucasus Mountains, with help from a force of Russian military led by Sergeant Kamarov. Following the rescue of the informant the SAS team intends to fly him to safety in Hamburg, Germany, but on the way their helicopter is shot down over Central Russia. An AC-130 gunship is dispatched to provide fire support for the team until they safely manage to evacuate from ultranationalist territory.

Soon after Al-Asad's coup, the United States invades the Middle Eastern country, using Marine Corps air cavalry to secure a local harbour. A platoon from the USMC 1st Force Recon led by Lieutenant Vasquez searches the city for Al-Asad, securing the television station broadcasting rebel propaganda, but failing to find the revolutionary leader. During the night, while the main USMC forces push Al-Asad's forces back to the capital city, Vasquez's men secure a disabled M1A2 Abrams main battle tank and escort it back to a highway. They are then airlifted to take part in what appears to be the final stages of the conflict, when United States Central Command is notified by the SAS of a Russian nuclear weapon nearby, and sends a team to disarm it. With Command ordering the evacuation of U.S. forces as a precaution, Vasquez's platoon helps to extricate an advance team pinned by enemy fire. The nuclear device nevertheless detonates, leveling large parts of the city and killing U.S. forces in the area. Vasquez and his squad were delayed from escaping the blast radius due to a last-minute rescue of a downed AH-1 SuperCobra pilot, and are aboard one of the helicopters caught in the blast radius. Jackson survives the crash of the CH-46 Sea Knight helicopter but dies soon thereafter

Price then has a flashback of his mission to eliminate Zakhaev in Prypiat, Ukraine15 years ago. In the aftermath of the Chernobyl disaster and the collapse of the Soviet Union, Zakhaev took advantage of the turmoil to profit from nuclear proliferation and used his new wealth to lure soldiers from the Soviet Army and form his Ultranationalist breakaway faction. Price, who was a lieutenant with the SAS, was paired with Captain MacMillan to carry out the black op assassination on the British government's orders. While Zakhaev was engaged in an arms deal, the SAS commandos used the opportunity to target him with a sniper rifle. Zakhaev survived, however, but lost his left arm. The Ultranationalist forces tracked the shot and pursued the snipers across the Zone of Alienation. During the chase, MacMillan was injured by a crashing helicopter they shot down, and Price was forced to carry him to the evacuation zone, narrowly escaping the enemy.

Returning to the present, the ultranationalists launch a counterattack against the SAS. From the village where the safehouse is, Captain Price's men briefly hold out against the assault with the aid of close air support from Marine AV-8B Harrier IIs before they are extracted by American forces, led by Staff Sergeant Griggs, who recently served alongside Sergeant Jackson in the USMC campaign in the Middle East. A joint operation, comprising of an SAS Regiment under the command of Captain Price, a USMC Force Recon unit led by Staff Sergeant Griggs, and forces from the Russian military led by Sgt. Kamarov, is undertaken to stop Zakhaev. They attempt to capture his son Victor to learn of his whereabouts, but the mission ends in failure when Zakhaev's son commits suicide after being cornered.

Zakhaev becomes enraged, blaming Western forces for the death of his son, and plans to retaliate by launching a series of SS-27 Topol M ballistic missiles with MIRV warheads at the East Coast of the United States from a missile base held by the ultranationalist forces. The ultranationalists are well-entrenched in the missile launch center, having earlier eliminated a group of Spetsnaz from the Russian military trying to retake the facility. The SAS/USMC operatives launch yet another joint mission to retake the facility, and starts off with the rescue of Griggs, who parachuted too far from the landing zone and were captured by enemy troops. They then disable the power to the facility, allowing a squad of USMC to breach an electrified fence. The squads meet up, but are shocked when Imran Zakhaev successfully launches two missiles (which would kill over forty million people). The operatives fight their way through the main gates, destroys a few BMP's, and enter the underground missile facility through a few air vents. The player now follows Cpt. Price to retake the missile control center, while the rest are told to capture the security center, which allowed Cpt. Price and his squad through a big reinforced blast door. The squad successfully deactivates the missiles before they reach their targets. Zakhaev's reinforcements, however, surrounds the missile silos and the joint force commandeers jeeps to make its escape.

During the escape, an enemy Mi-24D Hind gunship destroys a bridge the soldiers are attempting to cross, leaving them trapped. Zakhaev's troops arrive soon after, and begin engaging the remaining members of the strike force. A wrecked gas tanker on the bridge explodes, incapacitating everyone except Griggs. Griggs is then shot while trying to pull Soap to safety. Zakhaev himself arrives on the scene accompanied by two soldiers. Gaz and many other surviving members of the strike force are executed by Zakhaev and his men, and Zakhaev is on the verge of killing Soap too, but is distracted by the destruction of the Mi-24 Hind followed by the arrival of a Russian military Mi-28 helicopter. At this moment, a heavily wounded Captain Price slides his M1911 pistol to Soap, who then shoots and kills Zakhaev and his guards. Russian military forces arrive on the scene shortly afterwards. As MacTavish is medevac airlifted from the battleground on a Mi-8 helicopter, a Russian medic is seen desperately attempting to resuscitate Price.

After these events, news reports mention "nuclear missile tests" in Central Russia, "leadership struggles" arising in the ultranationalist party, and the attempt to locate a cargo ship lost in the Bering Strait has been called off, implying that the recent police actions in Russia were conducted in secret, and were not public knowledge.