Sewell played for the Alabama Crimson Tide in college, and was called up to the Cleveland Indians in 1920 after their starting third baseman Ray Chapman was killed in the major league's only on-field fatality. Sewell helped lead the Indians to the pennant, and played in 1,103 straight games from 1922 to 1930, the seventh-longest streak in history. During that time he also played for the New York Yankees. He was on the winning team in the World Series twice, once for Cleveland and once for the Yankees. His final major-league season was in 1933.
After retiring, Sewell worked in public relations for a dairy and scouted players for the Major Leagues. He coached the Alabama Crimson Tide baseball team for seven seasons from 1965 to 1972, compiling a career record of 114-99.
Sewell was inducted into the Alabama Sports Hall of Fame in 1970 as part of the hall's second class of honorees. In 1977 Sewell was inducted into the Baseball Hall of Fame. The University of Alabama's baseball stadium, Sewell-Thomas Field, is named after him. Sewell's brothers Luke and Tommy and his cousin Rip also played professional baseball.