On February 25, 1968, SOG operative Alex Mason is strapped to a chair in an interrogation room, bombarded with questions by his unseen captors about the location of a numbers station. Mason then recalls several events, as an attempt to answer their questions.
In 1961, Mason, Woods, and Bowman take part in Operation 40 to assassinate Fidel Castro in Cuba during the Bay of Pigs. Mason apparently succeeds and stays behind to protect the extraction plane from an oncoming blocade, before being captured by the real Castro, having shot a double. Handed over to General Nikita Dragovich to be held captive at Vorkuta Gulag, Mason befriends inmate Viktor Reznov, the former Red Army soldier. Reznov recounts to Mason the identities of his enemies, the same people involved in Mason’s torture: Nikita Dragovich, his right-hand man Lev Kravchenko, and ex-Nazi scientist Friedrich Steiner, who defected to the Soviet Union.
In October 1945, Reznov and Dimitri Petrenko were sent to extract Steiner from a Nazi base in the Arctic. Dragovich later betrayed them by testing Steiner's creation, a nerve agent known as "Nova-6", on Petrenko and other soldiers in a ship. Reznov was spared the same fate when British commandos, also attempting to acquire Nova-6, attacked the Soviets. During the confusion, Reznov destroyed the Nova-6 and escaped. However, the Soviets recreated it using Steiner and a British scientist, Daniel Clarke. Mason and Reznov later spark a prisoner uprising to escape the gulag, but only Mason escapes and Reznov is captured. One month later, President John F. Kennedy meets Mason and authorizes a mission to assassinate Dragovich. Mason briefly envisions aiming his side arm at Kennedy.
In November 1963, Mason, Woods, Bowman and Weaver are dispatched to Baikonur Cosmodrome, Kazakh SSR to disrupt the Soviet space program and eliminate members of "Ascension", a Soviet program giving sanctuary to Nazi scientists in exchange for their knowledge. Weaver is captured and Kravchenko stabs out his left eye. Mason and his team rescue him and destroy the Soyuz spacecraft, while Woods apparently kills Dragovich, though Mason believes him to be alive.
In 1968, the team is sent to Vietnam. After defending Khe Sanh, they recover a dossier on Dragovich from a Russian defector in Hue during the Tet Offensive. Mason finds the defector is none other than Reznov. They then penetrate Laos to recover a Nova-6 shipment from a downed Soviet plane. At the crash site the plane collapses and they are captured by Viet Cong and Spetznaz infiltrators. Bowman is executed, while Woods and Mason hijack an Mi-24 Hind and rescue Reznov at Kravchenko's base before confronting Kravchenko himself. Woods stabs Kravchenko, gaining the upper hand. But then as Kravchenko pulls the pins off four grenades strapped to his chest, Woods sacrifices himself by pushing Kravchenko and himself out a window. In a huge explosion, Mason presumes the two dead.
Meanwhile, Hudson and Weaver interrogate Clarke in Kowloon. Clarke reveals the location of a hidden facility in Mount Yamantau before being killed by Dragovich's men. Hudson and Weaver move to destroy the facility and receive a transmission from Steiner requesting to meet at Rebirth Island, as Dragovich has begun killing loose ends. Mason and Reznov head there to assassinate Steiner at the same time, succeeding just as Hudson and Weaver arrive. Mason is adamant that Reznov executed Steiner, but Hudson had witnessed Mason carrying out the act alone.
At this point, Hudson and Weaver are revealed as Mason's interrogators. Dragovich has communist sleeper cells placed all over the United States which, when ordered by the numbers broadcast, will release the Nova-6 gas. As a result, the U.S. is preparing a retaliatory strike on the Soviet Union, which will lead to a full scale war. Hudson needed Steiner to abort the gas launch but after his death only Mason has any knowledge of the numbers station. Hudson reveals that Dragovich brainwashed Mason to understand the numbers broadcasts, effectively making him a Soviet sleeper agent. It is revealed that the real Reznov never escaped and died during the Vorkuta break out, and that the Soviet defector in Hue was actually killed before Mason reached him. Mason’s visions of Reznov are a result of a dissociative disorder caused by the traumatic brainwashing program. Prior to the Vorkuta breakout, Reznov had secretly met and reprogrammed Mason to assassinate Dragovich, Kravchenko and Steiner for what they did to him and for killing Petrenko and his comrades, instead of Mason's original aim to kill the U.S. President. Mason finally remembers the location of the station: a Russian cargo ship called Rusalka off the coast of Cuba.
An assault on the Rusalka begins, with Mason and Hudson infiltrating the underwater submarine and broadcast station protected by the ship, intended to be used for an invasion of the U.S. 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 confront Dragovich in the lower levels of the facility. Dragovich taunts Mason and hints at his hand in assassinating Kennedy but Mason drowns him and escapes.
Archive footage of President Kennedy prior to his assassination is shown, revealing Mason in the crowd, implicitly suggesting that Mason may have carried out his initial programming.