Fox was born in St. Thomas Township, Pennsylvania. In his career he played with the Philadelphia Athletics (1947-49), the White Sox (1950-63), and the Houston Colt .45s and Astros. He was traded by the Athletics to Chicago on October 29, 1949.

With the White Sox, Fox worked alongside shortstops like Venezuelans Chico Carrasquel (1950-55) and hall-of-famer Luis Aparicio (1956-62), and was, year after year, a member of the strongest infield in the League. Only 5'9", he made up for his modest size and minimal power (he hit only 35 home runs in his career) with his good batting eye, excellent fielding, and baserunning speed. In 1959, he batted .306 and had an on base percentage of .380. Although not known as a great hitter (lifetime .288 batting average), he batted over .300 six times, with 2663 hits, 355 doubles, and 112 triples. He also led the league in singles for seven straight years, in triples once, and in hits four times. In addition, he won three Gold Gloves and was a twelve-time All Star.

Fox was not selected to the Hall of Fame in his initial period of eligibility. In his final opportunity, in 1985, he gained 74.6 percent of the vote when 75 percent was required for election by the Baseball Writers Association of America. However, the longtime disappointment of his admirers was finally relieved in 1997, when the Veterans Committee elected him to membership in the Hall.

Nellie Fox died of cancer in Baltimore, Maryland, at the age of 48.