[2] He played junior varsity basketball at Castro Valley High School for the legendary Coach Burns.

[3][4] After his sophomore season in 2007, he played collegiate summer baseball for the Yarmouth–Dennis Red Sox of the Cape Cod Baseball League, where he batted .341 in 39 games,[5] was named the starting catcher for the East Division All-Star team,[6] and helped lead the Red Sox to the league championship.

He also played for the United States national team in the 2009 Baseball World Cup in Nettuno, Italy.

[11] Shortly after the Futures Game, the Astros sent Castro home early from the Arizona Fall League so that he could rest for the 2010 season.

[9] On June 20, 2010, the Astros promoted Castro to the MLB from the Class AAA Round Rock Express.

He made his MLB debut on June 22, 2010, at Minute Maid Park against the San Francisco Giants.

On March 2, 2011, while playing in a spring training game against the Detroit Tigers, Castro suffered a knee injury while running to first base.

He underwent surgery two days later, on March 4, to repair his torn anterior cruciate ligament and a damaged meniscus.

On June 13, 2012, while pinch-hitting for Xavier Cedeño, Castro grounded out to Joaquin Arias to record the last out for Matt Cain's perfect game.

[16] In 2019, Castro played in only 79 games for the Twins due to sharing time with Mitch Garver, who had a breakout year.

[16] In Game 2 (October 16) of the American League Championship Series (ALCS) versus the Boston Red Sox, he hit a home run in a 9–5 loss.

[25] On June 29, 2022, Castro, along with ace Justin Verlander, helped lead a 2–0 shutout of the New York Mets.

Castro's two-run home run supplied all the offense in the game while tripling his RBI season total from one to three.

[27] On August 2, the Astros announced that Castro underwent surgery on the left knee and would miss the remainder of the season.