Castillo was called up by the Cubs on August 10, 2010, and spent seven games in the major leagues, hitting .300 with a home run, four doubles and five RBI.

On April 28, 2012, Castillo was recalled from Iowa after backup catcher Steve Clevenger was placed on the DL.

Castillo was the starting catcher for the Cubs in 2014, playing in 110 games and hitting .237/.296/.389 with 13 home runs and 46 RBI.

ESPN in December reported speculation that Castillo could be traded prior to the 2015 season, as the Cubs were expected to start newly acquired catcher Miguel Montero.

[4] On June 3, 2015, the Mariners traded Castillo, Dominic Leone, Gabby Guerrero, and Jack Reinheimer to the Arizona Diamondbacks in exchange for Mark Trumbo and Vidal Nuño.

in the month of April, Castillo played in 17 games for the Orioles, slashing .314/.333/.443 with six doubles, a home run and six RBI.

In a May 19 game against the Blue Jays, Castillo hit his first home run at Camden Yards as a member of the Orioles.

This streak ended the next night, however: he hit a go-ahead, game-winning three-run home run in the seventh inning to lead to Orioles to a 7–5 victory.

[8] On October 31, 2019, Castillo was traded to the Texas Rangers, along with international slot compensation, in exchange for Jonah McReynolds.

[11] Castillo appeared in 11 games for the Triple-A Rochester Red Wings, batting only .143/.351/.179 with no home runs and one RBI.