Having never thrown a pitch in the minor leagues, Pierce made his majors debut with the Detroit Tigers in 1945, just a few weeks after his 18th birthday. He was traded to the White Sox before the 1949 season.

In 13 seasons in a White Sox uniform, Pierce threw four one-hitters; pitched 51 consecutive scoreless innings and led the league in shutouts (7) and in strikeouts (186) in 1953; led the league in ERA (1.97) and in wins (20, along with Jim Bunning) in 1955; tied for the league lead in complete games between 1956 and 1958, and was selected for seven All-Star games.

Pierce had an excellent curve and a devastating change that he combined with an average fastball. He finished his career with the San Francisco Giants, winning 16 games with the 1962 Giants' pennant winners, and pitching a three-hit shutout against the Yankees in Game Six of the 1962 World Series.

In a 18-season career, Pierce posted a 211-169 record with 1,999 strikeouts and a 3.27 ERA in 3,336.2 innings. In addition, he completed 193 games with 38 shutouts and 32 saves in 585 games pitched (432 as a starter). His 186 career victories with the White Sox rank fourth on the club's all-time list, behind Hall of Famers Ted Lyons, Red Faber and Ed Walsh. His number 19 is one of only eight White Sox retired uniform numbers (1987) and he was named to the Sox Team of the Century (2000).

Maybe Pierce has been overlooked for the Hall of Fame honors during his time on the ballots, despite his considerable credentials are comparable to many of the pitchers enshrined in Cooperstown. Currently, at 78 of age, Pierce is a member of the White Sox community relations department, making frequent public appearances in the Chicago area. In addition, he heads the not-for-profit Chicago Baseball Cancer Charities.