Cepeda was born in Ponce, Puerto Rico. His father, slugger Pedro Cepeda, was a baseball legend in Puerto Rico and the Caribbean. Some called Cepeda the Babe Ruth of Latin America. Pedro's nicknames were Perucho and The Bull. Orlando became known as Peruchin and Baby Bull.

In his first season in 1958, Cepeda batted .312 with 25 home runs and 96 runs RBI, led the National League in doubles (38), and was named Rookie of the Year. In 1967, he was named the National League MVP by hitting .325 and driving in 111 RBIs. The Cardinals won the pennant that year and then went on to become World Champions by beating the Red Sox.

Cepeda was a 7-time All-Star (1959-64. 1967). He retired in 1975 after hitting a .297 BA with 379 homers and 1365 RBI in 17 seasons. Cepeda was the first designated hitter for the Boston Red Sox.

After retirement, Cepeda was caught while picking up a marijuana shipment in San Juan airport. This episode, and a related conviction, caused him to have an extremely difficult time getting voted into the Baseball Hall of Fame. By the early 1990s, when his time of eligibility was beginning to run out, many Puerto Ricans, commons and celebrities alike, began to campaign for his induction. Many of his backers alleged that other members of the Hall of Fame had done things equal or worse than drugs and were still inducted. Some international celebrities, former teammates and others also joined in the campaign to have Cepeda elected. In 1996, his last year of eligibility by voting, he came within two votes of becoming elected. Finally, in 1999, he was elected by the Hall's Veterans Committee, joining Roberto Clemente as the only other Puerto Rican in Cooperstown.

Cepeda was recognized nationally for his humanitarian efforts as an ambassador for baseball. He served as an honorary spokesman for the Crohn's and Colitis foundation of America, and participated in Athletes against AIDS.