De Aza was originally signed by the Los Angeles Dodgers as a non-drafted free agent on May 1, 2001. The Florida Marlins selected him from the minor league phase of the Rule 5 draft in 2004
In 2005, De Aza batted .286 with 34 stolen bases and 75 runs scored while playing for the Marlins' Single-A Jupiter affiliate. In 2006, De Aza batted .278 with 12 doubles, two triples, two home runs, 16 RBI and 27 stolen bases at Double-A.
On March 28, 2007, De Aza was named the starting center fielder for the Marlins, beating out Reggie Abercrombie, Eric Reed, and Alex Sánchez in what was seen as a surprise. In 2007, he batted .303 (10-for-33) in nine games for the Marlins before going on the disabled list on April 16 with a right ankle sprain; an MRI in mid-May revealed that his ankle had a hairline fracture. The fractured ankle required surgery and De Aza was placed on the disabled list for the 2007 season. De Aza was called up by the Florida Marlins in May 2009.
On October 21, 2009, the Chicago White Sox claimed De Aza off waivers from the Marlins. On July 27, 2011, he hit the first home run of his MLB career, off Detroit Tigers pitcher Max Scherzer.
On January 18, 2013, De Aza signed a one-year, $2.075 million deal to avoid arbitration with the White Sox. De Aza was the starting center fielder once again, and his main backups were Jordan Danks and DeWayne Wise. He would also periodically fill in at left field when Dayán Viciedo would be injured. In 153 games, he hit .264/.323/.405 with 17 HR, 62 RBI and 20 SB.
On March 31, 2014, De Aza recorded his first career multi-home run game in an Opening Day win over the Minnesota Twins.
On August 30, 2014, De Aza was traded from the Chicago White Sox to the Baltimore Orioles for minor league pitchers Miguel Chalas and Mark Blackmar. In his first five games with the Orioles, De Aza hit two home runs, had three RBI, stole a base, scored four runs and batted .400. He was designated for assignment on May 27, 2015.
On June 3, 2015, De Aza was traded to the Boston Red Sox for cash considerations and prospect Joe Gunkel.
On August 31, 2015, De Aza was traded to the San Francisco Giants with cash considerations for minor league pitcher Luis Ysla.
On December 23, 2015, De Aza signed a 1-year, $5.75 million contract with the New York Mets.
In 2016 he batted a career-low .205 in 130 games, and had a .297 on-base percentage, which was his lowest since his rookie season of 2007, and his .321 slugging percentage was his lowest since 2009. His average of a strikeout per every 3.99 plate appearances was the worst of his career. He did not have an assist in 76 games in the outfield, which were third most among NL outfielders without any assists.
On January 20, 2017, De Aza signed a minor league contract with the Oakland Athletics. He opted out of the contract near the end of spring training and became a free agent.
On June 14, 2017, De Aza signed a minor league deal with the Washington Nationals.
In 2013, De Aza played for the eventual 2013 World Baseball Classic winning team from the Dominican Republic, having a .208 batting average and 3 RBI in 8 games as a center fielder, going 1 for 3 in the final game against Puerto Rico.