The Kennedy administration continued seeking ways to oust Castro following the Bay of Pigs Invasion, experimenting with various ways of covertly facilitating the overthrow of the Cuban government. Significant hopes were pinned on the program of terrorist attacks and other destabilisation operations known as Operation Mongoose, devised under the Kennedy administration in 1961. Khrushchev learned of the project in February 1962, and preparations to install Soviet nuclear missiles in Cuba were undertaken in response.

Alarmed, Kennedy considered various reactions. He ultimately responded to the installation of nuclear missiles in Cuba with a naval blockade, and he presented an ultimatum to the Soviet Union. Khrushchev backed down from a confrontation, and the Soviet Union removed the missiles in return for a public American pledge not to invade Cuba again as well as a covert deal to remove US missiles from Turkey. Castro later admitted that "I would have agreed to the use of nuclear weapons. ... we took it for granted that it would become a nuclear war anyway, and that we were going to disappear."

The Cuban Missile Crisis (October–November 1962) brought the world closer to nuclear war than ever before. The aftermath of the crisis led to the first efforts in the nuclear arms race at nuclear disarmament and improving relations, although the Cold War's first arms control agreement, the Antarctic Treaty, had come into force in 1961.

In 1964, Khrushchev's Kremlin colleagues managed to oust him, but allowed him a peaceful retirement. Accused of rudeness and incompetence, John Lewis Gaddis argues that Khrushchev was also credited with ruining Soviet agriculture, bringing the world to the brink of nuclear war and that Khrushchev had become an 'international embarrassment' when he authorized construction of the Berlin Wall.