Negrón started his first professional season batting.234 in his first 25 games for the rookie class Gulf Coast League Red Sox. However, over the final 16 games he hit.292 with two home runs and 10runs batted in. He was promoted to the Class-A short seasonLowell Spinners on August 26. In 2007, Negron started the season with the Class-A Greenville Drive. He posted a.226 average with three home runs and 29 RBIs. He was promoted to the Class-A Advanced Lancaster JetHawks on August 31. He stole two bases in three games for the JetHawks. Back in Greenville for the 2008 season, Negrón hit.244 over 92 games. He showed his speed, stealing 25 bases and hitting five triples while scoring 50 runs. Negrón played three games for the Double-A Portland Sea Dogs during a brief July call-up and finished the season with the Lancaster JetHawks again. In 33 games, he hit.328 with seven home runs and 19 RBIs. The JetHawks made the playoffs, and Negrón went 10-for-39 with two homers and seven RBIs in nine games, capped off with a 10th inning, three run walk-off homer in game two of the California League semifinal series. Negrón showed strong numbers against left-handed pitching in 2008, hitting a combined.355 with a.600 slugging percentage. He finished the season with a total combined average of.265. He set career highs with eight home runs, 24 doubles and 46 RBIs. Negrón spent the first 111 games of his 2009 season with the Salem Red Sox, the new Class-A Advanced team of the Red Sox. He hit.264 with three homers and 34 RBIs.
Cincinnati Reds
Negrón was traded to the Cincinnati Reds on August 14, 2009, for shortstop Álex González and cash. After eight games with the Sarasota Reds, he was promoted to the Double-A Carolina Mudcats. He hit.241 in 54 at-bats. In 2010 for the Mudcats, Negrón hit.272 in 470 at-bats. Although his power numbers slightly dropped to six home runs and 41 RBIs, his on-base percentage increased to.344. He was promoted to Triple-A Louisville late in the season and went 4-for-21. Following the 2010 season, he played for the Peoria Saguaros in the Arizona Fall League and was placed on the Reds 40-man roster. He spent all of 2011 with Louisville, where he hit.216 in 123 games. Negrón began 2012 with Louisville, but was on June 6 he was called up for the first time to the Major Leagues, and made his Reds' debut the next day as a pinch-runner against the Pittsburgh Pirates. On June 14, he got his first Major League hit, a single off Scott Barnes, in the bottom of the fifth inning at Great American Ballpark in Cincinnati. He returned to Louisville after four appearances with the Reds, where he had the one hit in four at-bats. Negrón hit.218 with six homers and 20 RBIs at Louisville until he tore the anterior cruciate ligament and medial meniscus in his right knee on July 5, costing him the rest of the season. On November 30, 2012, he was non-tendered by the Reds and removed from the 40-man roster but he agreed to a minor league contract with them for the 2013 season that included an invitation to major league spring training. In 2013, all at Louisville, he hit.225 with five homers and 30 RBIs. He played for Criollos de Caguas in the Puerto Rican Winter League after the season. Playing in Louisville in 2014 and batting.269 for the Bats, in early July he was called up to the big leagues for the second time in his career, this time to fill in for the injured Brandon Phillips. On July 13, Negrón, who was starting at second base, hit his first big-league home run, off starter Francisco Liriano, and tallied his first three RBIs against the Pittsburgh Pirates. His playing time was significant for the injury-ravaged Reds; he made the most of it with a three-game stretch against the Cleveland Indians August 5–7, going a combined 7-15 with two doubles, one home run and five RBIs. On August 15 against the Colorado Rockies, he had his first four-hit game, going 4-4 with four singles and one RBI. Overall, he hit.271 with six homers and 17 RBI in 49 games for the Reds in 2014. In 2015, he split the season between Louisville and Cincinnati, hitting.216 in 59 games for Louisville and.140 in 43 games for the Reds. His season ended early when he suffered a partially dislocated shoulder, fractured scapula and torn labrum while making a catch at Great American Ball Park on September 8. He was released by the Reds in October and became a free agent.
After spending the off-season rehabbing from his shoulder injury, Negrón signed a minor league contract with the Chicago Cubs that included an invitation to spring training. He did not make the major league club and spent the entire season with the AAA Iowa Cubs, where he hit.256 in 117 games with nine homers, 46 RBI and 23 steals.
Arizona Diamondbacks
In November 2016, Negrón signed a minor league contract with the Arizona Diamondbacks. He was assigned to the Reno Aces of the Pacific Coast League, where he hit.300 in 120 games with 13 homers and 64 RBI. The Diamondbacks called him up to the majors in September He had four hits in 25 at-bats for the Diamondbacks that season in 14 games. He was added to the Diamondbacks roster for the Wild Card Game and 2017 NLDS but did not play. He was outrighted off the roster after the season but re-signed to a new minor league deal and invited to spring training. He was assigned to Reno to begin 2018, but was called up by the Diamondbacks on June 4, 2018 and appeared in two games for them on June 4 and June 5 against the San Francisco Giants, with one hit in three at-bats before he was designated for assignment on June 6 and outrighted back to the minors. He hit.283 in 118 games for Reno during the year.
Seattle Mariners
On August 30, 2018, Negrón was traded to the Seattle Mariners for cash considerations and he was added to the major league roster on September 1. He batted.219/.242/.313 for the year. For the season, he had the fastest baserunning sprint speed of all major league third basemen, at 29.5 feet/second. He was outrighted to the AAA Tacoma Rainiers on March 13, 2019 when he did not make the roster out of spring training In 82 games for Tacoma, he hit.310 wit 12 homers and 61 RBI. On July 16, the Mariners selected his contract and brought him back to the majors where he hit.217 in 10 games.
Los Angeles Dodgers
On July 28, 2019, Negrón was traded to the Los Angeles Dodgers in exchange for minor league infielder Daniel Castro. In his first at bat with the team, Negron hit a home run offKyle Freeland of the Colorado Rockies. He played in 30 games for the Dodgers, hitting.259.
Post playing career
Negrón announced his retirement from professional baseball on November 12, 2019. On November 19, 2019, Negrón was hired by the Seattle Mariners as assistant to the director of player development.
