Molitor played several positions during his career. He started out as a second baseman and then was moved to third base at the age of 25. During the latter half of his career, he was used primarily as a designated hitter. Molitor is the first, and as of 2006 only, player inducted into the Baseball Hall of Fame as a designated hitter.

Molitor was part of a young Milwaukee Brewers team that lost the 1982 World Series in seven games to the St. Louis Cardinals. Molitor batted .355 during the series. In Game 1 of the '82 Series, he had five hits, which set a Major League record. During the '82 season, he hit .302 and led the American League with 136 runs scored. Molitor also attracted national media attention during his 39-game hitting streak, which ended with "Molly" in the on-deck circle when the winning, game-ending run was scored against the Cleveland Indians on August 26, 1987. He had several seasons early in his career which were severely shortened by injuries, including 1980, 1981, 1984, 1986 and 1987. After moving to designated hitter, his injury problems seemed to go away. Molitor was acquired through free agency by the Toronto Blue Jays in December 1992 and was a key part of the Blue Jays second World Championship. Molitor won the World Series MVP Award award for hitting .500 in the series. He left the Blue Jays after the 1995 season and joined his home town Minnesota Twins for the final three seasons of his career. Molitor relished his opportunity to play with Twins superstar Kirby Puckett, but as fate would have it, Puckett developed glaucoma during spring training in 1996 and never played another game.

Molitor's lifetime statistics include 2,683 games played, 1,782 runs scored, 3,319 hits, 234 home runs, 1,307 runs batted in, a .306 batting average, and 504 stolen bases. He batted .368 in 5 postseason series and was an all-star seven times. He was also the first and, so far, only member of the 3,000-hit club to reach 3,000 with a triple.

On June 11, 1999, the Brewers retired Molitor's uniform number 4. During the ceremony at Milwaukee County Stadium, Molitor announced that if he went into the Hall of Fame, he would do so as a Brewer. On January 6, 2004, he was elected to the Hall in his first year of eligibility, with 85.2f the votes. True to his word, he joined Robin Yount as the only Hall of Famers to be depicted on their plaques with Brewers caps.

In 1999, Molitor ranked No. 99 on The Sporting News' list of the 100 Greatest Baseball Players, and he was nominated as a finalist for the Major League Baseball All-Century Team. Yount also was a finalist for the All-Century Team but did not make the TSN 100 list.

Molitor once was "pantsed" by a mascot while playing in a regular-season game for the Blue Jays. Considering he was wearing polka-dot underpants, it is safe to assume this was deliberate, and an example of the eccentric camaraderie Toronto players sometimes had.