In the year 2025, a Special Forces unit led by David Mason with his partner, Harper, arrive at "The Vault", a secret location that is home to the aged Frank Woods, who they believe has information on the whereabouts of Raul Menendez. Woods admits that Menendez visited him, and gives Mason a locket that Menendez had left behind. Woods narrates all of the 1980s missions to David Mason.
In 1986, Alex Mason has retired from active duty and is living in Alaska with the seven year-old David. Their already strained relationship is put to the test when Mason is approached by Jason Hudson, seeking to recruit him for a mission in Angola. Woods' unit has been taken captive while aiding rebels in the country's civil war, and their actions have been disavowed by the CIA. Hudson enlists Mason for a covert mission to rescue Woods and any survivors from his unit, with the help of the Jonas Savimbi, the leader of the UNITA forces, at war with the MPLA. They discover Woods is the only survivor. They discover Menendez at a radio among a contingent of Cubans while attempting sneak into a village in MPLA territory to contact friendly forces, but are discovered by the enemy, allowing Menendez to flee. Savimbi returns by helicopter to rescue Woods, Mason, and Hudson. Woods later reveals to David Mason that that Menendez was responsible for his captivity.
In light of the events in Angola, Mason and Hudson begin tracking Menendez, who has set himself up as one of the primary arms suppliers for conflicts in Africa and Latin America. Later that year, the CIA tracked down and authorizes a strike against Menendez who was running guns in Afghanistan where the war between the Soviets and the Mujahideen took place for his private army. At this point, the story begins to explore Menendez's motivations and his vendetta against the West. After he and his sister were accidentally burned in the fire-bombing of a warehouse as part of an insurance scam, the Menendez family turned to drug trafficking and built up power and influence throughout Nicaragua. Their actions did not go unnoticed, and the CIA sanctioned the assassination of his father. Now knowing that Menendez considers the conflict to be personal and that he will not back down, the CIA lean on Panamanian president Manuel Noriega to support a raid on Menendez's home in Panama. Menendez suffers further tragedy when an enraged Woods inadvertently kills his sister with a grenade during the raid. Menendez himself manages to escape due to secret assistance from Noriega.
Menendez plans to retaliate against those he holds responsible for his sister's death. During the 1989 invasion of Panama, he kidnaps Jason Hudson and David Mason, using them as bait for a trap. He then uses Hudson to mislead Woods, manipulating him into shooting Mason instead of himself. Depending on the player's actions in Afghanistan, it is implied that Menendez had used moles within the CIA. If the player disobeys Hudson's instructions to shoot Alex Mason in the head and instead shoots him in the leg, he will survive and reappear in the game's ending. In the ensuing chaos, Menendez kills Hudson and cripples Woods. Unsatisfied with his revenge, Menendez allows Woods and David to live, promising to return to complete his revenge when the time is right.
Three decades later, Menendez re-emerges as the leader of Cordis Die, a massive populist movement with over a billion followers. He stages a cyberattack that cripples the Chinese Stock Exchange; in response, the Chinese ban the export of rare earth elements, fermenting the start of a new Cold War between the Chinese-led Strategic Defense Coalition (SDC) and the U.S.-led JSOC. Taking advantage of this stand-off, Menendez attempts to bring the two powers to a full-blown war by inciting conflicts between the two, secretly aiding SDC leader Chairman Tian-Zhao, who worked with Mason and Woods during their operation in Afghanistan in 1986. Using the intelligence provided by Woods, David, now a Navy SEAL code-named Section, leads JSOC forces in the renewed search for Menendez.
Shortly after gathering intelligence from Woods, Section and JSOC infiltrates Myanmar investigating a spike in activity in the region. There, Section's team encounters a computer engineer under Menendez's employment, warning them of a cyberattack with a Celerium device, a quantum computer capable of hacking any computer system. Section's team is later deployed in Pakistan, attempting to gather intelligence on Menendez's plots. During the infiltration, Menendez discloses the name of a target, "Karma" in the Cayman Islands. Section and SEAL operatives Harper and Salazar later infiltrate the Cayman Islands, finding out that "Karma" is a woman named Chloe Lynch, a former employee of Menendez's shell corporation, Tacitus. Lynch was the main developer of the Celerium device, and as a means of wrapping up loose ends, Menendez had deployed mercenaries for her abduction.
JSOC later has a lead on Menendez in Yemen, where JSOC asset Farid infiltrates Menendez's cell to help Section facilitate the leader's capture. The player, as Farid has a choice during the mission. Menendez, suspecting Farid's disloyalty, orders him to shoot the captured Harper. If the player chooses not to shoot Harper, and instead attempts to shoot Menendez, he fails, but Harper survives and is rescued. If the player chooses to shoot Harper, Farid survives, and Harper is not present in any conversations or missions thereafter. Menendez is successfully captured, but this was a ruse for Menendez to hack into the U.S. military's computer infrastructure on the aircraft carrier the U.S.S. Obama, seizing control the the United States' entire drone fleet. Salazar is revealed to be Menendez's mole within JSOC, and facilitates Menendez's attack—Menendez escapes with Salazar's aid, and when Menendez breaks in to the bridge of the Obama, Salazar shoots the soldiers guarding Admiral Briggs, with Lynch's survival dependent on Farid's survival in the previous mission. The player, playing as Menendez, has the choice of either killing or wounding Admiral Briggs. If the player only wounds Briggs, and during the course of the campaign, the JSOC and SDC enter an alliance, then the player is later informed that the SDC sent hundreds of drones to defend the Obama, and consequently Briggs was able to save the ship and its crew. Menendez uses the drones to stage an attack on Los Angeles during a meeting of G20 leaders, hoping to kill them and cause catastrophic damage to the global economy. Mason escorts the President of the United States to safety amidst the drone attacks.
JSOC eventually finds the source of the transmissions responsible for the hacking to Haiti, where Section leads JSOC forces into recapturing the facility in the final mission, and apprehending or killing Menendez. There are different endings depending on the actions the player takes throughout the campaign, such as whether or not the United States and China are able to enter an alliance with each other, as well as determining the fates of certain individuals in the game.
During the main campaign, the player may choose to participate in optional Strike Missions. The Strike Missions involve JSOC attempting to curb the SDC's global influence by preventing them from forcing neighboring countries into the alliance. Section himself does not participate in these missions directly, though he can command the forces remotely from a command center. If the missions are completed successfully, the SDC is weakened enough to ally with JSOC, and assists the player later in the campaign, for example, in sending its own drones to rescue the U.S.S. Obama.