He played most notably at shortstop, in Major League Baseball (MLB) for the New York Mets, Miami Marlins, Toronto Blue Jays, and Colorado Rockies.

[5][3][6] Reyes spent the first two months of the 2003 season with the Norfolk Tides of the Triple-A International League, where he batted .269 and stole 26 bases in just 42 games.

[2] Injuries to Mike Piazza and Mo Vaughn had contributed to the Mets' poor performance in the National League East, and eventually convinced manager Art Howe to begin playing some of the team's younger talent.

Reyes made his major league debut on June 10, 2003, against the Texas Rangers, the day before his 20th birthday, going 2-for-4 with a pair of runs scored in a 9–7 loss.

Reyes' season was cut short a month early by a sprained ankle, but he still managed to compile impressive rookie numbers.

However, a back problem for Reyes and injuries to other key Mets players led to a collapse and instead of being involved in a pennant race, the team found itself fighting to stay out of last place in the division.

[12] As the 2006 season wound down, Reyes was in pursuit of an unusual feat — reaching 20 home runs, 20 triples, 20 doubles, and 20 stolen bases.

In November 2006, Reyes participated in the Major League Baseball Japan All-Star Series along with teammates John Maine and David Wright.

He hit a two-run walk-off home run in the 10th inning of Game 5, giving the MLB team their first sweep of their NPB rivals.

On July 12, 2007, Reyes hit the ninth leadoff home run of his career against Cincinnati Reds pitcher Bronson Arroyo, setting a new record for the franchise.

On the second-to-last day of the regular season he was involved in a benches-clearing brawl against the Florida Marlins, which started when Miguel Olivo charged across the diamond and threw a punch at Reyes.

One of the casualties of this change of focus was the "Professor Reyes" segment played between innings at Shea where he taught the fans Spanish words and phrases.

Reyes finished the season with a batting average of .297, with 72 extra-base hits (including a majors-leading 19 triples), 68 RBIs and 56 stolen bases.

A few days before spring training, Mets manager Jerry Manuel announced that he was considering moving Reyes from the leadoff spot to 2nd or 3rd in the line-up.

[33] On November 19, 2012, Reyes was traded to the Toronto Blue Jays along with Josh Johnson, Mark Buehrle, John Buck, and Emilio Bonifacio, in exchange for Jeff Mathis, Adeiny Hechavarria, Henderson Álvarez, Yunel Escobar, Jake Marisnick, Anthony DeSclafani, and Justin Nicolino.

[34] Reyes needed to be carted off the field during a game against the Kansas City Royals on April 12, 2013, after hearing a pop in his left ankle while sliding into second.

On April 15, general manager Alex Anthopoulos reported that an MRI scan revealed no fracture and that no surgery would be required, but that Reyes was expected to miss three months.

[35] On April 15, CBS Sports reported that Reyes's ankle injury was less severe than originally thought, reducing his time on the DL to eight weeks,[36] but that was later refuted by Blue Jays management.

After experiencing a minor hamstring strain during spring training, Reyes began the 2014 season batting leadoff for the Blue Jays.

In his first at-bat on Opening Day he aggravated his hamstring injury while running to first base, and was placed on the 15-day disabled list at the end of the game.

[32] On July 27, 2015, Reyes was traded to the Colorado Rockies, along with Jeff Hoffman, Miguel Castro, and Jesús Tinoco, in exchange for Troy Tulowitzki and LaTroy Hawkins.

Overall in 2015, combined with both teams, Reyes played 132 total games with a .274 batting average, 24 stolen bases, 19 home runs, and 53 RBI.

[54] On September 22, Reyes hit a two-run home run in the bottom of the 9th inning in a pivotal game against the Philadelphia Phillies to even the score at 6–6.

Asdrúbal Cabrera would later hit a three-run home run in the 11th inning to win, 9–8, propelling the Mets to a Wild Card berth.

[55] After 60 games with the Mets in 2016, the club picked up its option on its contract with Reyes, keeping him with the team for the major league minimum salary in 2017.

[56] Prior to the 2017 season, Reyes began working out as a full-time utility player, playing the infield and center field.

[74] On February 23, 2016, MLB Commissioner Rob Manfred announced that Reyes would be placed on paid administrative leave until at least April, when his trial began.

[75] On March 30, 2016, prosecutors in Maui moved to dismiss the domestic abuse charges on the grounds that his wife was refusing to cooperate as a witness.

[79][80] On December 7, 2007, Reyes was announced as the cover athlete for Major League Baseball 2K8 from 2K Sports, taking over from New York Yankees counterpart Derek Jeter.

Reyes was also the cover athlete for the Nintendo DS spinoff, Major League Baseball 2K8 Fantasy All-Stars, albeit in cartoon form.