In Cuba, the 26th of July Movement, led by young revolutionaries Fidel Castro and Che Guevara, seized power in the Cuban Revolution on 1 January 1959, toppling President Fulgencio Batista, whose unpopular regime had been denied arms by the Eisenhower administration. Although Fidel Castro's first refused to categorize his new government as socialist and repeatedly denying being a communist, Castro appointed Marxists to senior government and military positions. Most significantly, Che Guevara became Governor of the Central Bank and then Minister of Industries.

Diplomatic relations between Cuba and the United States continued for some time after Batista's fall, but President Eisenhower deliberately left the capital to avoid meeting Castro during the latter's trip to Washington, D.C. in April, leaving Vice President Richard Nixon to conduct the meeting in his place. Cuba began negotiating for arms purchases from the Eastern Bloc in March 1960. In March of that year Eisenhower gave approval to CIA plans and funding to overthrow Castro.

In January 1961, just prior to leaving office, Eisenhower formally severed relations with the Cuban government. That April, the administration of newly elected American President John F. Kennedy mounted the unsuccessful CIA-organized ship-borne invasion of the island at Playa Girón and Playa Larga in Santa Clara Province—a failure that publicly humiliated the United States. Castro responded by publicly embracing Marxism–Leninism, and the Soviet Union pledged to provide further support. In December, the US government began a campaign of terrorist attacks against the Cuban people and covert operations and sabotage against the administration, in an attempt to overthrow the Cuban government.