- Raul Menendez is the primary antagonist of the game. He is a Nicaraguan political activist who rose to prominence during theproxy wars of the 1980s. He is responsible for the deaths of both Alex Mason and Jason Hudson. He reappears in the year 2025 as the leader of “Cordis Die”, a populist political party that commandeers the automated armies that form the United States military, and proceeds to turn them against their former masters. At the end of the game, he is either killed or captured alive by David Mason, depending on the player’s choice. He is voiced and motion captured by Kamar de los Reyes.
- DeFalco is the secondary antagonist, Menendez’s right-hand man, Second-in-command of Cordis Die and the leader of a mercenary army that works for Menendez and Cordis Die. DeFalco is a ruthless killer who kills with no mercy. DeFalco is killed by Section either in “Karma” when Section, Harper, and Salazar saves Lynch or in “Judgement Day” while Section saves Harper from Menendez, Defalco, and a henchman or he is killed in “Odessyes” by Farid. He is voiced by Julian Sands
- Tian Zhao (Chinese: 赵天) is the leader of the Chinese-led organization, Strategic Defense Coalition (SDC), and secretly an ally of Menendez. He previously worked with Alex Mason and Frank Woods during the mission in Afghanistan in 1986, assisting the Mujahideen in repelling a Soviet Invasion. In 2025 he led the SDC in building a military coalition in the region to counter the West’s own military strength with countries such as Russia, Iran, Afghanistan, and India as its allies. Depending on the actions involving the Strike Force missions, if the player succeeds in repealing the SDC invasion then the player can assassinate him in the last stage. If the player however fails in preventing the invasion then Tian survives and the named countries join the SDC. He is voiced by Byron Mann.
- Salazar is a Nicaraguan secondary character. He is part of JSOC and a member of David Mason’s team during the 2025 Campaign. He grew up in Nicaragua during the rise of Raul Menendez. Towards the end of the campaign it is discovered Salazar was actually working for Menendez all along and helps him escape from the USS Obama after he was captured by David Mason. He will surrender peacefully but will be executed by Harper if Harper is alive. He is voiced by Celestin Cornielle.
- Manuel Noriega is the former Commander of the Panamanian Defense Forces and a supporting antagonist. He was the de facto military governor of Panama from 1983 to 1989. He aids the CIA to capture Raul Menendez by sending the PDF to his plantation. The PDF captures him, but Noriega later betrays his own men by helping Menendez. He is the objective of Operation Just Cause. Alex Mason and Frank Woods are sent to look for him in the outskirts of the Panama City. He is captured, but Jason Hudson later informs that he is an HVI and must be taken safely to a US Army checkpoint for a prisoner exchange.
- Lev Kravchenko (Russian: Лев Кравченко) is the ex-second-in-command of Nikita Dragovich, revealed to now be working with Raul Menendez. He survived the events of Call of Duty: Black Ops but is killed by either Frank Woods or Alex Mason during the mission in Afghanistan.