He appeared in 1,399 games, primarily as a left fielder, in Major League Baseball (MLB) for the Cincinnati Reds (1941–1942, 1945, 1948–1949), Chicago Cubs (1949–1955), St. Louis Cardinals (1956), and New York / San Francisco Giants (1957–1959).

During a time when the Cubs were especially moribund, Sauer provided some joy for the team's fans with his power hitting, earning him the nickname "The Mayor of Wrigley Field".

[1] One of the highlights of Sauer's tenure in Chicago occurred during the 1952 Major League Baseball All-Star Game, played July 8 at Shibe Park, Philadelphia.

Starting in left field for the National League, Sauer came to bat in the fourth inning with the NL trailing 2–1 and Stan Musial on first base.

When the game was called due to rain after it had completed the mandatory five innings, the NL was awarded the 3–2 victory and Sauer's homer stood as the winning blow.

He signed as a free agent with the Giants, and in 1957, the club's last year in New York City, he slugged 26 home runs in 127 games, finishing tenth in the Senior Circuit in long balls.

He played two more years with the franchise in San Francisco before becoming a coach late in 1959, and then a long-time scout and roving minor league batting instructor for the Giants.