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In the year 2025, US Special Forces operatives led by David Mason and his partner, Harper, arrive at "the Vault", a top-security location home to an elderly Frank Woods, whom they suspect possess vital information on the whereabouts of Raul Menendez. Woods concedes that Menendez has recently visited him, and shows them a locket that the latter had left behind. Frank then narrates several covert missions undertaken during his military career which span their previous encounters.
In 1986 Alex Mason had effectively retired from active duty to pursue an obscure existence in Alaska with his son, the seven-year-old David. Their shaky relationship is further strained when Mason is solicited by Jason Hudson, seeking to recruit him for an assignment in Cuando Cubango during the height of the Angolan civil and South African Border Wars. Woods had disappeared with his men while aiding Jonas Savimbi's UNITA rebels against Angola's Marxist government; their actions have already been disavowed by the CIA and Hudson hopes to rescue any survivors. With UNITA assistance, Mason and Hudson recover Woods from the Kavango River, subsequently locating Menendez among a contingent of Cuban military advisers. However, a firefight breaks out, and their quarry escapes as the Americans are rescued by Savimbi in a Hind D. It is revealed that Menendez is responsible for holding Woods captive after murdering his team.
In light of this information, Mason, Woods, and Hudson begin tracking Menendez, who has established himself as a primary arms dealer for bush conflicts in Southern Africa and Latin America. Later in the year, the CIA authorizes a strike against the unscrupulous Nicaraguan, now making a healthy profit running arms across Soviet-occupied Afghanistan. In Afghanistan, Mason, Woods, and Hudson assist the Mujahideen in their battle against the Russians, along with Chinese operative Tian Zhao. Woods and Mason find Lev Kravchenko, who turns out to have survive the grenade incident with Woods in Vietnam, causing Mason to see the numbers and hearing the voice of Viktor Reznov again.
Kravchenko is interrogated by the group and the player is given the option of executing Kravchenko by Reznov's orders inside Mason's head or resisting and finishing the interrogation, in which case, Woods then executes Kravchenko after admitting that he associated with Menendez and that he has men inside the CIA. Regardless of how Kravchenko is killed, the Mujahideen are revealed to be allied with Menendez, and double-cross Mason, Woods, Hudson, and Zhao. The four are beaten, tied, and left for dead in the middle of the desert, unconscious until rescued by two unknown civilians, one of whom Mason believed to be Reznov.
At this point, Menendez's motive for his seemingly senseless vendetta against the West become clear: his beloved sister was grievously injured in an act of arson committed by American businessmen for insurance money. The Menendez clan, which dominates a powerful drug cartel, was again rocked by loss when the CIA sanctions the assassination of Raul's father. An embittered Menendez now considers the conflict to be personal, but his one-man struggle against the West is interrupted when Mason, Woods, Hudson, and the Panama Defense Force raid his headquarters in Nicaragua; an enraged Woods inadvertently kills Raul's sister with a grenade.
Faking his demise with the assistance of Panamanian dictator Manuel Noriega, Menendez lives to retaliate against those he holds personally responsible for his sister's death. During the 1989 invasion of Panama, he utilizes moles in the CIA to kidnap Hudson and David, using them as bait for a trap. He then uses Hudson to mislead Woods, manipulating him into shooting Mason instead of himself. If the player disobeys Hudson's instructions to shoot Alex Mason in the head and instead shoots him anywhere else, 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 after the Invasion of Panama, 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 which the entire infrastructure of the US Army runs and relies on, fermenting the start of a new Cold War between the United States and NATO, against the Chinese-led SDC (Strategic Defense Coalition). 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. 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 Barack Obama, seizing control of 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 the player has completed all of the Strike Force missions, 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. Section 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, forming an alliance between the United States and China, with the Chinese assisting the player later in the campaign, for example, in sending its own drones to rescue the U.S.S. Obama and sending its forces to assist JSOC in Haiti.
The storyline of Call of Duty: Black Ops II has several possible endings. The one shown depends on decisions and tasks completed over the course of the game. If the player spares Menendez's life, completes all four Strike Force Missions, and the characters Chloe Lynch and Alex Mason survive the events of the game, then the preferred ending will result. The player will have secured an alliance between China and the United States, ending the Second Cold War. Lynch's survival prevents Menendez's cyberattack from succeeding. And finally, Mason's survival allows him to visit Frank Woods in retirement, reuniting with Section. The final scene shows Menendez in prison becoming enraged after watching a talk show with Jimmy Kimmel interviewing Lynch, who insults him during the interview.
If Menendez is spared, Lynch survives, but Mason is killed in action, then the Second Cold War will end, and Menendez's cyberattack will fail. However, Section will visit his father's grave with Woods and decide to retire from soldiering. Woods comments that his father would approve of the decision.
If Menendez is spared and Lynch is killed, Section will apprehend Menendez taking him into custody. The cyberattack will, however, succeed, allowing Menendez to escape. He kills Woods in the retirement home before visiting his sister's grave, dousing himself in gasoline and readying a lit match.
If Menendez is killed regardless of Lynch and Mason's fate, a YouTube video that Menendez recorded earlier will air, inciting the civilian population to riot and burn down the White House.
If the players complete the game once, players can unlock the non-canonical Special Ending. The ending showing Menendez and Woods having some practice in the backroom with Avenged Sevenfold. They then perform at Club Solar together, with Menendez playing the guitar and Woods on the drums. Several characters from the game also make an appearance in the cheering crowd.