He played in Major League Baseball (MLB) for the Texas Rangers, Oakland Athletics, and Chicago White Sox.

Andrus debuted in the major leagues in 2009 as the Rangers' Opening Day starting shortstop at the age of 20.

Andrus defended the left side of the Rangers' infield next to third baseman Adrián Beltré for eight years, forming a friendship that was noted for the former's practical jokes on the latter.

[7][8] On July 31, 2007, Andrus, Jarrod Saltalamacchia, and three minor league pitchers (Matt Harrison, Neftalí Feliz, and Beau Jones) were traded from the Braves to the Rangers for Mark Teixeira and Ron Mahay.

[9] With Rangers shortstop Michael Young agreeing to move to third base in 2009, Andrus earned the starting job on Opening Day.

[11][12] On May 20, Andrus and second baseman Ian Kinsler turned a triple play, with Kinsler catching a line drive and throwing to Andrus, who stepped on second base to put out a runner who failed to tag up and then tagged a runner who had left first base.

In the World Series, his performance plummeted, batting .176 with zero extra base hits as the Rangers lost to the San Francisco Giants.

[16] In the 2011 postseason, he hit .235 with one double and one base on balls as the Rangers again won the American League pennant but lost the World Series, this time to the St. Louis Cardinals.

[16] In the 2012 American League Wild Card game, he hit two singles and grounded into a double play as the Rangers fell to the Baltimore Orioles.

[16] He had a career-high 42 stolen bases, which tied for third in the AL.[20] Andrus began the 2014 season with an 11-game hitting streak[21] that ultimately ended when he was ejected on April 13.

[26] Andrus finished 2015 with career lows in batting average (.258), on-base percentage (.309), and sacrifice hits, while posting a then-career-best seven home runs and stealing 25 bases for the AL West champion Rangers.

In 2017, he posted a career-best offensive season, hitting .297 with 20 home runs and 88 RBIs and 25 steals in 158 games.

[16] Andrus ended his tenure with the Rangers as the franchise's career leader with 305 stolen bases and 105 caught steals.

[35] On February 6, 2021, Andrus and Aramis Garcia were traded to the Oakland Athletics for Khris Davis, Jonah Heim, and Dane Acker.

[36][37] In his first year in Oakland, Andrus batted .243/.294/.320 with 3 home runs, 37 RBIs, and 12 stolen bases in 146 games.

[38][39] Finances contributed to the Athletics decision, as Andrus was 164 plate appearances from earning a $15-million player option for the following season.

[41] He hit better in his 43 games in Chicago than he earlier in the season in Oakland, posting a .773 on-base plus slugging percentage with the White Sox, 100 points higher than he had with the Athletics.

[42] On April 5, Andrus recorded his 2,000 career hit, a single off Logan Webb of the Giants that snapped an 0-for-14 hitless streak.

[45] In the final game of his MLB career, he went hitless in five at-bats and scored Chicago's only run in a 2–1 loss to the San Diego Padres.

[47] On March 3, 2024, Andrus signed a minor league contract with the Arizona Diamondbacks with an invitation to spring training.

[54] In 2012, Andrus donated $12,500 to OurCalling, a Christian charity that helps homeless people in Dallas County.