Boudreau was an eight-time All Star Game selection, starting three times. He won the 1944 AL batting title (.327), and led the league in doubles in 1941, 1944, and 1947. He led AL shortstops in fielding eight times. Boudreau still holds the record for hitting the most consecutive doubles in a game (four), set on July 14, 1946.
While still at Illinois, Cleveland Indians general manager Cy Slapnicka paid him an undisclosed sum in return for agreeing to play baseball for the Indians after he graduated. His father complained to the Big Ten Conference, and league officials ruled him ineligible for collegiate sports. During his senior year at Illinois, he played pro basketball with the Hammond Ciesar All-Americans of the National Basketball League.
Boudreau made his major league debut on September 9, 1938 for the Cleveland Indians at 21 as a first baseman in his first game. In 1939, Indian manager Ossie Vitt told him that he would have to move from his normal third base position to shortstop since established slugger Ken Keltner already had the regular third base job.
In 1940, his first full year as a starter, he batted .295 with 46 doubles and 101 RBI, and was chosen for the All-Star Game.
He helped make history in 1941 as a key figure in stopping the 56-game hitting streak by Joe DiMaggio. After two sparkling stops by Keltner at third base on hard ground balls earlier in the game, Boudreau snagged a bad-hop grounder to short barehanded and started a double play retiring DiMaggio at first. He finished the season with a modest .257 average but a league-leading 45 doubles. He turned 134 double plays in 1944, the most ever by a player-manager in major league history.
After the 1941 season, owner Alva Bradley promoted manager Roger Peckinpaugh to general manager and appointed the 25-year-old Boudreau player-manager. He managed the Indians throughout World War II. Playing basketball had put a strain on Boudreau's ankles that turned into arthritis, which classified him as 4-F and thus ineligible for military service. When he bought the Indians in 1947, Bill Veeck, after being approached by Boudreau, renewed the player-manager agreement with mixed feelings on both sides. Despite personal contentiousness, they won the 1948 World Series, Cleveland's first championship in 28 years and only the second (and as of 2014[update] its last) in its history, with Boudreau and Veeck publicly acknowledging each other's role in the team's success.
Released by the Indians as both player and manager following the 1950 season, Boudreau signed with the Boston Red Sox, playing full-time in 1951, moving up to player-manager in 1952 and managing from the bench in 1953–54. He then became the first manager of the Kansas City Athletics in 1955 after their move from Philadelphia until he was fired after 104 games in 1957 and replaced by Harry Craft. He last managed the Chicago Cubs, in 1960.
Boudreau was elected to the Baseball Hall of Fame in 1970 with 77.33% of the vote. That same year, his uniform number 5 was retired by the Cleveland Indians (he wore number 4 with the Red Sox).
Boudreau is credited with inventing the infield shift, which came to be known colloquially as the "Boudreau shift." Because slugging Red Sox superstar Ted Williams was a dead-pull hitter, he moved most of his Cleveland Indian fielders to the right of second base against the Splendid Splinter, leaving only the third baseman and left fielder to the left of second but also very close to second base, far to the right of their normal positions. With characteristic stubborn pride, Teddy Ballgame refused the obvious advice from teammates to hit or bunt to left against the Boudreau shift, but great hitter that he was, not changing his approach against the shift didn't affect his hitting very much.
Boudreau later admitted that the shift was more about "psyching out" Williams rather than playing him to pull. "I always considered the Boudreau shift a psychological, rather than a tactical [ploy]," he declared in his autobiography Player-Manager.
Cubs broadcasters, June 11, 1981 – Vince Lloyd, Lou Boudreau, Milo Hamilton, Jack Brickhouse
Boudreau did play-by-play for Cub games in 1958-59 before switching roles with manager "Jolly Cholly" Charlie Grimm in 1960. But after only one season as Cubs manager, Boudreau returned to the radio booth and remained there until 1987. He also did radio play-by-play for the Chicago Bulls in 1966–68.
The presence of a Hall of Fame announcer affected at least one game. On June 23, 1976, the Cubs were two runs behind at home in the fourth inning of the second game of a doubleheader against the Pittsburgh Pirates when the umpires called the game on account of darkness (since there were no lights at Wrigley Field until 1988), announcing that the game would be resumed at the same point the next day as was normally the case in those days. But Boudreau knew the rules better than anyone else in the park, it turned out, for he went down quickly to the clubhouse and pointed out to the umpires that a game that was not yet an official game and hence could not be treated as suspended game (i.e., it had not gone five innings, or four and a half with the home team leading, as neither was the case), and as such had to be replayed from the first pitch (as was then the rule in a rainout). The umpires called the National League office, found Boudreau was right, and wiped out the two-run Cubbie deficit. 
Boudreau married Della DeRuiter in 1938, who bore him four children. His daughter Sharyn married Denny McLain, a former star pitcher with the Detroit Tigers who was the last 30-game winner in the major leagues (31-6 for the world champion 1968 Detroit Tigers).