Picking up where the last game left off, Nikolai takes John Price and John “Soap” MacTavish to a safehouse in India to tend to the latter’s knife wound. However, Vladimir Makarov finds where the safehouse is and has his men attack the Loyalists protecting Price and Soap to tie up loose ends. Thanks to a former Spetsnaz soldier named Yuri, Price and Soap are safely taken out of India and go into hiding. Meanwhile, the Russian invasion of America continues, with the American soldiers pushing the Russians into New York. Delta Force’s Team Metal, led by Sandman, destroys a Russian radio jammer and infiltrates a Russian Oscar-II class submarine. Inside the submarine, Sandman and Frost launch the sub's missiles towards the other Russian warships, crippling the Russian army and navy and driving them out of the U.S. as with their navy decimated and the U.S. back on the offensive, Russia orders a full retreat and withdrawal from the U.S. East Coast, returning to the Motherland in humiliated defeat.
Three months later, Russian President Boris Vorshevsky flies to Hamburg to discuss a peace treaty with the West as the war has gone too far. However, Makarov’s men hijacked Vorshevsky’s plane and kidnapped the latter for the nuclear codes. When Vorshevsky refuses to give them up knowing that if Makarov gets access to the Russian nuclear arsenal, he could ignite World War III, Makarov has his men search through the wreckage for the former’s daughter, Alena, to use as leverage. While they did not find Alena, Makarov still has the President and plans on a Russian Invasion of Europe.
In response to Makarov’s reappearance, Price and a healed-up Soap decide to start their mission of stopping the former. With Yuri joining the duo due to his own hatred of Makarov, they go to Sierra Leone to stop a transport of precious cargo from being delivered to Europe. However, they fail, and Makarov is able to distribute the cargo across Europe, which turned out to be chemicals that covered the entire continent. This allows the Russians to start their invasion of the Western European countries, requiring the US military to come and help them out with NATO military forces crippled by Makarov's chemical attacks.
Meanwhile, Price contacts his former captain Macmillan, who was promoted long after the events of Pripyat. Price convinces Macmillan to give him intel on Makarov, and the latter points him in the direction of African warlord Waraabe. Price’s team storms Waraabe’s base in Bosaso, Somalia and interrogates the latter on what he knows about Makarov. Waraabe reveals that he only knows Makarov through the latter’s contact Volk, who is hiding in Paris after the chemical attacks. Somewhat satisfied with what they got, Price’s group leaves after the former kills Waraabe in honour of the SAS members who died in the chemical attacks.
Price gets in contact with Sandman as the two have worked together in the past, and the former tells the latter about Volk’s location. Thanks to Price’s intel, Team Metal is able to secure Volk and interrogate the latter for Makarov’s whereabouts. Volk tells Sandman that Makarov is in Prague, using the Hotel Lustig as a meeting spot for his top men. Thanks to the Czech Resistance led by Kamarov, one of Price and Soap's allies from the Russian Loyalists back during the Second Russian Civil War, Price’s group splits off into different directions and Soap and Yuri set up sniping positions. However, Makarov anticipated their plan and executed Kamarov with C4s in an attempt to kill Price. While Price makes it out safely, Soap and Yuri are forced to jump out of their compromised hut as a C4 planted there earlier by Makarov explodes. While they survive the fall, Soap’s chest wounds reopen, forcing Price and Yuri to drag him to safety. Unfortunately, Soap loses too much blood during the trip and dies in front of Price and Yuri. In his final breath, Soap tells Price that Makarov recognized Yuri. In a mixture of grief and fury, Price punches Yuri down a flight of stairs and demands to know why Makarov knows the latter.
With no other options, Yuri explains how he knew Makarov. The two were with Imran Zakhaev in Pripyat twenty years ago when the latter tried to sell nuclear material. When Price shot Zakhaev’s arm off, Makarov and Yuri managed to get the latter out of the scene, therefore being responsible for Zakhaev’s survival. Makarov and Yuri received promotions due to saving Zakhaev, but Makarov soon became too enthralled with his new position among the Ultranationalists, especially with his hatred towards the Western countries. Fifteen years after Pripyat, Makarov and Yuri were in Iraq watching the USMC’s ill-fated attempt at finding Khaled Al-Asad, and it turns out the former was responsible for ordering the nuclear bomb to detonate, killing 30,000 soldiers. Yuri was horrified and disgusted that his friend would go that far, and five years later, he tried to stop Makarov from committing his massacre at the Zakhaev International Airport. However, Makarov discovered Yuri’s treachery and shot the latter point-blank with a Desert Eagle to prevent him from stopping him. Yuri tried to stop his former friend in the lobby, but he was too wounded to do so and passed out, awakening to find surviving airport security guards and first responders finding him and getting him medical attention. Afterwards, Yuri swore revenge against Makarov, joining the Loyalists sometime later before meeting Soap and Price. After hearing Yuri’s story, Price reluctantly keeps him around as he needs help to take down Makarov.
Price and Yuri head to a castle in Prague to find Makarov’s location and sneak through the area while killing members of the latter’s Inner Circle. They overhear Makarov interrogating President Vorshevsky for the launch codes, revealing that his men managed to find the latter’s daughter Alena in Berlin. Team Metal is sent to extract Alena to safety, but Makarov’s men get to her first and take her away. With time running out, Team Metal (minus Frost who did not come for some reason) team up with Price and Yuri to find President Vorshevsky and Alena in an abandoned diamond mine in Siberia. Both Alena and the President are successfully rescued, but Team Metal sacrifices their lives to make sure Price and Yuri leave safely with the President.
With his freedom regained, President Vorshevsky makes peace with the United States, and the war across Europe ends. But with Makarov still alive, and now a wanted fugitive by all involved parties, including the US, UK, Russian Federation, NATO, and possibly even the UN, Price swears to put an end to the terrorist once and for all for everything he did and for everyone who died because of him, including Soap. Nikolai tracks Makarov to a hotel on the Arabian Peninsula, and Price and Yuri storm the place, killing the last of Makarov’s men as they make it to the rooftop. Price stops Makarov’s helicopter from taking him out of the area, but the latter gets on his feet and prepares to execute the former. Yuri stops Makarov but is killed by the latter. However, Price uses this opportunity to wrap a noose around Makarov and smashes the window panning below them. Makarov is hanged and instantly dies, and Price lights a cigar, satisfied that his vengeance is complete and the last of Imran Zakhaev’s men, and the Four Horsemen in Makarov, Imran and Viktor Zakhaev, and Khaled Al-Asad, are gone.
