Sewell made his major league debut in 1920 with the World Series champion Cleveland Indians and became the team's full-time shortstop the following year. An emerging star, Sewell batted .318 with 101 runs, 93 RBI and a .412 on base percentage in 1921. Sewell's patience and daily work ethic became his hallmarks over the following decade and a half. Playing with Cleveland until 1930 and the New York Yankees from 1931 to 1933, Sewell batted .312 with 1141 runs, 1055 RBI, 49 home runs and a .391 on base percentage. He regularly scored 90 or more runs a season and twice topped the 100 RBI plateau. He hit a career high 11 home runs in 1932.

Of more historical significance, Sewell struck out a mere 114 times in 7132 career at-bats for an average of one strikeout every 63 at-bats, the lowest average of any major league player in history. He also holds the single season record for fewest strikeouts over a full season, with 3, set in 1932. Sewell also had 3 strikeouts in 1930, albeit in just 353 at-bats (as opposed to 503 in his record-setting year), as well as three other full seasons (1925, 1929, 1933) with 4 strikeouts. He struck out ten or more times in only four seasons, and his highest strikeout total was twenty, during the 1922 season. For his 1925-1933 seasons, Sewell struck out 4, 6, 7, 9, 4, 3, 8, 3, and 4 times.

Sewell also played in 1,103 consecutive games played, which was the second-longest streak to that point after Everett Scott.

Sewell played in two World Series, in 1920 and 1932, winning both times. He was inducted into the Baseball Hall of Fame in 1977 by the Veteran's Committee.