On February 25, 1968, SAD/SOG operative Alex Mason is strapped to a chair in an interrogation room. Unaware of his whereabouts, he is bombarded with questions by his unseen captors about the location of a numbers station. Most of the missions in the game are presented as flashbacks between 1961 and 1968.
In 1961, Mason, Woods, and Bowman attempt to assassinate Fidel Castro during the Bay of Pigs invasion of Cuba as a part of Operation 40. Mason apparently succeeds in the assassination, but their exfiltration goes awry, with Mason staying behind to protect the extraction plane. He is captured by the real Castro, having shot a double. Because of an alliance with the Soviet Union, Castro hands Mason over to General Nikita Dragovich. Mason is then held captive at Vorkuta Gulag for two years. During his imprisonment, Mason befriends Viktor Reznov, a former Red Army soldier. Reznov recounts to Mason the identities of those involved in Mason's torture: Dragovich, Lev Kravchenko (his right-hand man) and Friedrich Steiner, an ex-Nazi scientist who defected to the Soviet Union. All three share a connection to Reznov: in October 1945, Reznov, Dragovich, Kravchenko, and Dimitri Petrenko were a part of a unit sent to locate Steiner, hiding with a unit of the SS in the Arctic Circle. During the operation, Reznov was betrayed by Dragovich, who used Steiner's creation, a nerve agent known as "Nova-6" on Petrenko. Reznov was spared the same fate when British commandos attacked the Russians. During the confusion, he destroys Nova-6. However, it was later recreated by Steiner and a British scientist named Daniel Clarke for the Soviets. Shortly afterward, Reznov is imprisoned in Vorkuta. Mason and Reznov spark a prisoner uprising to escape the gulag, but only Mason escapes.
One month later, President John F. Kennedy authorizes the assassination of Dragovich. In November 1963, Mason, Woods, Bowman and Weaver are dispatched to Baikonur Cosmodrome in the Kazakh SSR to disrupt the Soviet space program and eliminate members of the Soviet Ascension program. At the start of the operation, Weaver is captured and Mason sees Kravchenko torture him, stabbing his left eye, but Mason and his team later rescue him, while still destroying the Soyuz spacecraft as well. Dragovich eludes assassination, prompting Mason to search for him over the next five years. By 1968, the MACV-SOG was established in Vietnam to investigate the Soviets' presence. After defending Khe Sanh, the SOG is deployed to Hue during the Tet Offensive to recover a dossier with information on Dragovich from a Russian defector. The team recovers the dossier, while Mason encounters Reznov, who is revealed to be the defector. The SOG then penetrates Laos to recover a Nova-6 shipment from a downed Soviet plane. At the crash site, they are overwhelmed by waves of Viet Cong and Spetznaz soldiers, eventually getting captured. Mason and Reznov escape, but Bowman is executed and Woods dies while killing Kravchenko.
Meanwhile, Hudson and Weaver interrogate Dr. Daniel Clarke, the engineer who stabilized Nova-6, in Kowloon. Clarke identifies Steiner as part of the conspiracy, and reveals the location of a hidden facility in Mount Yamantau before being killed by Dragovich's men. Hudson and Weaver head to Mount Yamantau to destroy the facility and apprehend Steiner. During the mission, Hudson receives a transmission from Steiner requesting to meet him at Rebirth Island in the Aral Sea to learn how to halt a numbers broadcast that would send instructions to sleeper agents to release Nova-6 gas in American cities. Mason and Reznov head to Rebirth Island to assassinate Steiner. In the present, Mason is adamant that Reznov executed Steiner, but Hudson had witnessed Mason carrying out the deed. At this point, Hudson and Weaver are revealed as Mason's interrogators. Hudson realizes that Dragovich brainwashed Mason to understand the numbers broadcasts, effectively becoming a Soviet sleeper agent. Out of options, Hudson deliberately sets Mason free in order to follow him. It is revealed that the real Reznov died during the Vorkuta break out, and Mason's visions of Reznov are a result of a dissociative disorder caused by the traumatic brainwashing program. Reznov had, in fact, reprogrammed Mason to assassinate Dragovich, Kravchenko and Steiner instead of President Kennedy prior to the Vorkuta breakout. Hudson plays the numbers recording for Mason a final time, prompting him to remember the location of the Russian cargo ship Rusalka off the coast of Cuba.
By dawn, the team launches an assault on the Rusalka, with Mason and Hudson infiltrating an underwater broadcast station protected by the ship, a Soviet submarine station intended to be used as a staging point for US invasion after the planned Nova-6 attack. Confirming that the Rusalka is the numbers station, Hudson calls in the US Navy to destroy the ship and its underwater base. Mason and Hudson finally find Dragovich in the lower levels of the facility and manage to kill him before the destruction of the base, swimming for the surface during the destruction of the targets. Weaver declares victory, but Mason is unsure, haunted by his last conversation with Dragovich.
Archive footage of President Kennedy prior to his assassination are shown, with the broadcaster and Mason narrating random numbers. After a second play-through of the archive footage, Mason's appearance in the crowd, as well as Dragovich's final words suggest that Mason followed his original programming and assassinated Kennedy.