The game's campaign follows Modern Warfare 2 and begins right after the events of its final mission. Similar to Modern Warfare 2, it is centered around the Task Force 141, which contains Captain Price, Soap MacTavish, and Yuri, one of the playable characters. Alongside the Delta Force and Special Air Service, they hunt Vladimir Makarov (antagonist of Modern Warfare 2), a Russian terrorist who leads the Russian Ultranationalist party. He leads several terror attacks across Europe, triggering a large-scale war between the Ultranationalists and friendly forces.

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Hours after killing General Shepherd, Price and a critically wounded Soap evacuate with Nikolai to a Russian loyalist safe-house in Himachal Pradesh, but soon encounter enemy forces sent by Makarov to kill them. They are extracted from the region with the help of Yuri, a man with a common grudge against Makarov. Meanwhile, in the United States, an American four-man Delta Force team, call-signed Metal 0-1, manages to repel Russian Forces in New York City by blowing up the Russian spectrum jamming tower on top of the Wall Street Stock Exchange and hijacking an Oscar II-class submarine to launch cruise missiles at the Russian Navy, forcing the Russians to withdraw from the East Coast.

Two months later, Makarov attacks a plane en route to Hamburg containing the President of Russia, Boris Vorshevsky, to derail his planned peace treaty with the United States. After killing several members of the F.S.O., Makarov reveals to the Russian president that he intends to have Russia dominate Europe by using its nuclear arsenal. Vorshevsky refuses to give over the launch codes, so Makarov targets his daughter, Alena, to force him. Makarov subsequently has chemical bombs transported from Sierra Leone to ensure his plan succeeds. The bombs are detonated in every NATO-affiliated country's major cities, despite the efforts of a SAS team attempting to stop an attack in London.

The attacks cripple the intelligence networks and military bases in Europe, allowing the Russians to quickly conquer much of the continent. In turn, the U.S. sends in counter-attack forces to repel the invasion. Team Metal launches a rescue operation to rescue the Vice President of the United States after he is captured while en route to a peace conference in Hamburg, Germany. During the chaos, Price's team gets a lead from his former commanding officer, MacMillan, leading them to Somalia, where they learn from the leader of a terrorist group the identity of the bomb maker as Volk, the CEO of Fregata Industries. After Team Metal receives the location from Price, they capture Volk in Paris with the help of the GIGN and other U.S. forces, though the battle causes the Eiffel Tower to collapse.

Metal Team also assists Price in finding Makarov. With the assistance of loyalist Russian forces and Czech partisans, Price's team attempts to assassinate Makarov in Prague, but a forewarned Makarov thwarts it and counter-attacks. Soap is mortally wounded and dies after revealing to Price that Yuri is known by Makarov. Holding Yuri at gunpoint, Price learns that Yuri and Makarov were allies, helping evacuate Imran Zakhaev in Pripyat after Price wounded him. After the nuclear detonation in the Middle East, a sickened Yuri defected and was critically shot by Makarov shortly before the airport massacre in Moscow. Price grudgingly maintains their alliance.

After infiltrating Makarov's castle base near Prague and learning of President Vorshevsky's captivity, Price alerts Metal that Alena Vorshevsky has been discovered at a safe house in Berlin. Though Metal fails to rescue Alena, she is tracked to Vorshevsky's location. Metal leads a joint task force with Price and Yuri to a Siberian diamond mine. They manage to rescue the Vorshevskys, but the mine then collapses. Metal operatives Sandman, Grinch, and Truck sacrifice themselves in the last stand, ensuring that Price and Yuri escape with the Vorshevskys. The peace treaty is finally signed, withdrawing Russian forces from Europe and ending the hostility between the U.S. and Russia.

Despite the end of the war, Price and Yuri continue their hunt for Makarov, finally tracking him down to a hotel in Dubai in January 2017. With Nikolai's help, the pair assaults the hotel armed with heavy equipment in an attempt to avenge Soap. After being forced to abandon an injured Yuri, Price prevents Makarov from escaping by crashing his helicopter into the hotel's atrium. Makarov prepares to execute Price with a Desert Eagle, but Yuri intervenes, which sees him killed by Makarov. Enraged, Price ties a steel cable around Makarov's neck and breaks the glass roof of the hotel, hanging and killing the ruthless terrorist. As the police begin to arrive at the hotel, a victorious Price smokes a cigar.