Minoso was signed by the Cleveland Indians as an amateur free agent in 1948. Between 1949 and 1964 he played for the Tribe (1949, 1951, 1958-59), Chicago White Sox (1951-1957, 1960-61, 1964, 1976, 1980), St. Louis Cardinals (1962) and Washington Senators (1963). On May 1, 1951, in a game against the New York Yankees in Comiskey Park, the speedy Minoso became the first black player to wear a White Sox uniform.

In 1976, after several years playing in Mexico, Minoso returned to play three games with the White Sox. He picked up one single in eight at bats, becoming the oldest player ever to get a base hit in the major leagues (53); he returned to appear in two more games with the Sox in 1980. His five stints with Chicago cemented his image as a local baseball icon for at least three generations of Chisox fans.

In his major league career, and despite not playing regularly until he was 28, Minoso hit for a .298 BA, with 186 home runs, 1023 RBI, 1136 runs, 1963 hits, 336 doubles, 83 triples, 205 stolen bases, 814 walks and 192 hit by pitch. His .389 on base percentage and .459 slugging average, combined for a solid .848 OPS, is a clear indication of how valuable a player Minoso truly was.