After his senior year at Brother Rice, he was selected by the Detroit Tigers of Major League Baseball (MLB) in the 2007 MLB draft in the 41st round. He did not sign with the Tigers so that he could attend college.

The Chicago Cubs selected LeMahieu in the second round of the 2009 MLB draft with the 79th overall selection. He played for the Peoria Chiefs of the Class A Midwest League in 2009 after the draft. In 38 games, he hit .316 with 30 RBIs. He spent the 2010 season with the Daytona Cubs of the Class A-Advanced Florida State League, batting .314 with 73 RBIs and 15 stolen bases in 135 games, going on to earn a FSL Post-Season All-Star selection.

On December 8, 2011, the Cubs traded LeMahieu and Tyler Colvin to the Colorado Rockies for Casey Weathers and Ian Stewart. He began the 2012 season with the Colorado Springs Sky Sox of the PCL.

On May 23, 2012, LeMahieu was called up to the major leagues to replace injured Jonathan Herrera as a utility infielder. He returned to Colorado Springs when Herrera was activated, and was recalled to the Rockies on July 17 when Chris Nelson was hospitalized. On August 14, he recorded a career-best four hits in a 9–6 Rockies win over the Milwaukee Brewers and in his first game against his former team, the Chicago Cubs, LeMahieu registered three hits in four at bats. Later in August, LeMahieu wrote his name into the record books, as he recorded 12 assists in a 9-inning victory against the Los Angeles Dodgers on the 28th. This mark tied a record held by several players.

LeMahieu finished the 2019 season batting .327 with 26 home runs and 102 RBIs in 145 games. He set new career highs in hits (197), doubles (33), home runs, RBIs, runs scored (109), slugging percentage (.518), OPS+ (135), total bases (312), fWAR (5.4), and bWAR (5.9). He had the lowest pull percentage of all major league batters (27.9%) and posted remarkably consistent stats all-round (his lowest monthly batting average was .282 in July, while his home/road and pre/post All-Star splits were .338/.318 and .336/.316 respectively). Additionally, besides ranking second in the American League in batting average behind Tim Anderson, he became the first Yankee to qualify for the batting title with a .300+ batting average since Robinson Canó in 2013, and posted the highest batting average for a Yankee player since Derek Jeter hit .334 in 2009. LeMahieu was awarded the Silver Slugger Award for the first time in his career, was named to the inaugural All-MLB First Team for second base, and finished fourth in the AL MVP voting behind Mike Trout, Alex Bregman, and Marcus Semien.

In 2014, LeMahieu batted .267/.315/.348 with five home runs in 494 at bats. Defensively, he had an ultimate zone rating of 11.0, which was first in the National League (NL) and third in the majors. He won his first Gold Glove with 16 Defensive Runs Saved and led the majors with 99 double plays.

LeMahieu and his wife, Jordan, were married in 2014. On July 4, 2020, it was announced that LeMahieu had tested positive for COVID-19, but recovered shortly after.

LeMahieu was the starting second baseman for the NL in the 2015 All-Star Game; this was LeMahieu’s first All-Star selection. For the season, he batted .301 and led the majors in percentage of balls hit to the opposite field (39.0%), while seeing the highest percentage of fastballs of all MLB hitters (66.9%).

In 2016, LeMahieu won the NL batting title after batting .439 in August and .363 in September. His .348 season average led all of MLB. For the season, he had the highest batting average on balls in play (.388) of all major league players, and again led the majors in percentage of balls hit to the opposite field (37.9%).

LeMahieu ended the season with a .364 batting average, which was the highest in the American League, and also led the AL in OBP (.421) and OPS (1.011), as well as fewest errors by a second baseman (4). He was the fourth Yankee to lead the majors in hitting and the ninth Yankee to win an AL batting title. LeMahieu was also the second player ever to win a batting title in each league. (LeMahieu led the NL in 2016 with a .348 average playing for the Colorado Rockies). The other player is Ed Delahanty, who hit .410 for Philadelphia (NL) in 1899 and .376 for Washington (AL) in 1902. However, LeMahieu became the first player in MLB’s “modern era” to win a batting title in both the American and National Leagues. With teammate Luke Voit leading the MLB with 22 home runs in 2020, the duo became the first pair of teammates to lead the MLB in batting average and home runs since Hank Aaron (.355) and Eddie Mathews (46 HR) did it in 1959 with the Milwaukee Braves. He also became the first Yankees player since Paul O’Neill in 1994 to had won a batting title in a shortened season before entering contract negotiations. LeMahieu won his second straight Silver Slugger Award and finished third in AL MVP voting.

LeMahieu was selected to the 2017 MLB All-Star Game as an injury replacement for Dee Gordon. He batted .310 and for the third consecutive year led the majors in percentage of balls hit to the opposite field (38.3%), while seeing the highest percentage of fastballs of all MLB hitters (67.0%). Also again in 2017, LeMahieu collected the NL Gold Glove for second basemen. Additionally, he won the Fielding Bible Award for all major league second basemen.

In the 2018 season, LeMahieu hit a career-high 15 home runs while batting .276/.321/.428. He was tied for seeing the highest percentage of fastballs of all MLB hitters (63.6%). In addition to an increase in power numbers, his defensive excellence continued. LeMahieu finished the 2018 season with a 19.5 SDI (SABR Defensive Index) highest of all NL players, and his 2.2 defensive WAR was eighth best among all of MLB. The .993 fielding percentage, .859 zone rating and 18 defensive runs saved were best for all NL second basemen. He earned both a third Gold Glove and a third Wilson Defensive Player of the Year Award.

On January 14, 2019, LeMahieu signed a two-year, $24 million deal with the New York Yankees. The Yankees anticipated using LeMahieu as a utility infielder. He made his Yankees debut on March 30 at Yankees Stadium, picking up a pair of hits and an RBI in four at-bats in a 5–3 loss to the Orioles. After getting off to a fast start, LeMahieu had an electric month of June. He reached base safely in all but two games, and also put together a 14-game hitting streak from June 14 to June 30 (including six consecutive multi-hit games from June 23-30). In the two-game London Series (which marked the halfway mark of the Yankees season) at the end of June, LeMahieu had seven hits in 12 at bats, three doubles and seven RBIs. This performance helped the Yankees sweep the Red Sox in the series. This won LeMahieu his first career Player of the Week award. He then followed it up by winning the June AL Player of the Month Award for the first time (batting .395/.434/.658 with 6 home runs, 29 RBIs, 26 runs scored, and 45 hits) and being elected as the starting second baseman for the All-Star game.

Despite his 6’4″, 215 pound frame that led many scouts to suggest that he had potential as a pure power hitter, LeMahieu became a powerful opposite field contact hitter. His tendency to not leg kick, and hit for contact with low launch angle (average of under 10 degrees) was compensated by his high exit velocity (91.7 mph average as of August 8, 2019), meaning he can still hit for extra bases while not getting long fly outs. He has also hit more opposite field home runs than pulling home runs in the 2019 season.