He played in Major League Baseball (MLB) for the Atlanta Braves, Arizona Diamondbacks, New York Yankees and Miami Marlins.

Prado took full advantage of the opportunity, to the extent that he remained the starter at second, batting second in the lineup, even after Johnson's return to the active roster.

Prado told reporters that he lost 14 pounds during the 2010 off-season doing the P90X fitness program, and is starting spring training stronger and "more agile.

[9] In late September, Prado suffered from a hip pointer, and an MRI revealed that he had a torn external oblique, causing him to miss the remainder of the season and the playoffs.

In the 2010–11 off-season the Braves acquired former Florida Marlins starting second baseman Dan Uggla in a trade for Omar Infante and reliever Mike Dunn.

On July 26, 2011, in a game against the Pittsburgh Pirates that ended with a controversial call on a play at home plate, Prado went 0-for-9 and left eight men on base.

[4] After the 2012 season, the Braves traded Prado with Randall Delgado, Nick Ahmed, Zeke Spruill and Brandon Drury to the Arizona Diamondbacks for Justin Upton and Chris Johnson.

[4] On July 31, 2014, Prado was traded to the New York Yankees in exchange for catching prospect Peter O'Brien and a player to be named later.

On September 16, 2014, Prado underwent an emergency appendectomy, resulting on the Yankees putting him on the 60-Day Disabled List, ending his season.

On December 19, 2014, the Yankees traded Prado and David Phelps to the Miami Marlins for Nathan Eovaldi, Garrett Jones, and Domingo Germán.

[19] Prado's 2017 and 2018 seasons were severely hampered by a series of different injuries which landed him on the disabled list seven separate times.

On March 26, 2017, the Marlins placed Prado on the 15-day disabled list due to a Grade 1 hamstring strain, an injury he suffered during the 2017 World Baseball Classic.

[22] Upon his return in May, Prado struggled at the plate and only hit .194 before straining his left hamstring in a game on May 25 and was placed on the 10-day disabled list.