He was a professional pitcher between 1949 and 1963, although he served in the United States Army during 1953 and 1954. "Vinegar Bend" began his Major League Baseball career with the St. Louis Cardinals in 1952, continuing through 1953, and then again (following military service) from 1956-60. Mizell was twice named an All-Star as a Cardinal, as he was named to both National League teams in 1959 (in those days, two All-Star games were played in a season). Mizell did not appear in either game. Mizell then joined the Pittsburgh Pirates from 1960–1962, winning one championship, and spent time with the expansion New York Mets in 1962 before retiring.
His trade to the Pittsburgh Pirates on May 28, 1960 is considered one of the catalysts towards the Pirates championship run that season. Mizell went 13-5 for the Pirates that season, and finished sixth in the National League in winning percentage. One of the players traded for Mizell, Julian Javier, would go on to be one of the mainstays of the St. Louis Cardinals championship teams of the 1960s.
In a nine-season career, Mizell was 90-88 with a 3.85 ERA in 268 games, 230 of which were starts. He pitched 61 complete games, including 15 shutouts. He allowed 654 earned runs and struck out 918 in 1528 and 2/3 innings pitched. Mizell appeared in two World Series games in 1960 (Game 3 as a starter, Game 6 in relief), going 0-1 with a 15.43 ERA, with 2.1 innings pitched.