He has previously played in Major League Baseball (MLB) for the Chicago Cubs, New York Yankees, Miami Marlins and Washington Nationals.

In 2009, Castro was named to the Florida State League All-Star team, and won MVP honors, going 4-for-4 with an inside-the-park home run in the game.

Later in the game he hit a triple with the bases loaded, setting the record for most runs batted in (RBIs) in a major league debut with six.

[11] On September 23, 2011, Castro got his 200th base hit of the season, at Busch Stadium against the rival St. Louis Cardinals, and was the youngest member of the Cubs to ever do so.

In August, Castro and the Cubs agreed to a contract extension through the 2019 season with a team option for 2020, with total guaranteed compensation of $60 million.

Unfortunately, Castro's All-Star year came to an early end when he was injured on September 2 when he awkwardly slid into home plate in a game against the Milwaukee Brewers.

[16] Castro was the top hitting shortstop (for batting average) in the National League ahead of the Dodgers' Hanley Ramírez.

During a game on April 20, 2015, against the Pirates in Pittsburgh, Castro hit a ball that went foul behind home plate and struck a fan in her head.

[21] In August, Castro was benched by Cubs manager Joe Maddon due to poor performance, including a career low .236 batting average.

On April 28, 2017, Castro hit a game tying 2-run home run in the 9th inning of an eventual 14–11 Yankees comeback win against the Baltimore Orioles.

On December 11, 2017, Castro was traded to the Miami Marlins (along with Jorge Guzmán and José Devers) in exchange for outfielder Giancarlo Stanton and cash considerations.

Castro's performance improved late in the season and he finished with a .270 batting average and set new career highs with 22 home runs and 86 RBI.

[34] On July 23, 2020, Castro was the starting second baseman, making his Nationals debut on Opening Day against his former team, the New York Yankees.

In an August 14 game against the Baltimore Orioles, Castro suffered a broken wrist attempting to make a diving play in the sixth inning.

[43][44] On November 2, a dispersal draft was held for the other ALPB teams to get an opportunity to select players who were under contract with the Ghost Hounds.

[45] On July 16, 2021, Major League Baseball announced it had begun an investigation into domestic violence allegations that had been brought against Castro, and he was placed on administrative leave.

[46] On July 30, Castro was suspended 30 games without pay and fined an undisclosed amount for violation of the league’s joint domestic violence policy.