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.

The protagonist of Black Ops, Alex Mason returns as the protagonist in the Cold War section, where he will be fighting in proxy wars for the United States in the Cold War.

Call of Duty: Black Ops III takes place in a dystopian future set in 2065, 40 years after the events of Black Ops II. Several countries around the world have developed high-tech air defenses that render air assaults useless.