The competition was the brainchild of Venezuelan baseball entrepreneur Pablo Morales and Oscar Prieto Ortiz, who devised the idea after seeing the success of the Serie Interamericana in 1946, which featured the clubs Brooklyn Bushwicks from the United States, Cervecería Caracas from Venezuela, Sultanes de Monterrey from Mexico, and an All-Star team composed of Cuban players.

Inspired by the Interamerican Series and his experience as a former president of the International Baseball Federation, Morales joined Prieto and presented the idea to baseball representatives of Cuba, Panama, and Puerto Rico during a meeting held in Havana on August 21, 1948. The representatives then agreed to stage a four-country, round-robin tournament 12-game to be known as the Serie del Caribe, to be launched in Cuba from February 20–25 of 1949.

The Series ran annually from 1949 through 1960, with Cuba winning seven times. However, the event was suspended in 1961, as a result of the Cuban Revolution. Fidel Castro dissolved all professional baseball in Cuba, and MLB Commissioner Ford Frick ruled that American major leaguers were barred from playing in Havana, where the 1961 series had been scheduled.

It was not until 1970 that the Caribbean Series was revived. Moreover, the 1981 Caribbean Series was not held due to a Venezuelan League player's strike.

The tournament featured the champions of the Dominican Republic, Mexico, Puerto Rico, and Venezuela for over 40 years. Cuba returned in 2014. Panama returned to host the 2019 edition. Colombia was added for the 2020 edition, replacing Cuba who could not participate due to visa issues. Curaçao was invited as a guest in 2023.