In 2021, he was selected to play in the All-Star Game, won the Silver Slugger Award, and was named to the All-MLB Second Team.

[4] Castellanos transferred to Archbishop McCarthy High School in Southwest Ranches, Florida, before his junior year.

In the 2009 Under Armour All-America Baseball Game, played at Wrigley Field, he scored three runs, had four doubles and three RBIs, winning Most Valuable Player honors.

[7] Castellanos played for the United States national baseball team for individuals 18 years of age and under in the 2009 Pan American Junior Championships, in which he batted .356 with six doubles and nine RBIs, leading all players with 14 runs scored, as the team won the gold medal.

[8] The Detroit Tigers selected Castellanos in the second round, with the 44th overall pick, in the 2010 Major League Baseball draft.

[6] With Castellanos now playing left field on a full-time basis, the Tigers optioned him to the Toledo Mud Hens of the Class AAA International League at the start of the 2013 season.

[30] However, he received infrequent playing time, as the Tigers were in a pennant race and manager Jim Leyland preferred to use players with more major league experience.

[32] Dave Dombrowski, the general manager of the Tigers at that time, said that they would shift Miguel Cabrera to first base, and use Castellanos as their starting third baseman for 2014.

Through the All-Star break of the 2016 season, Castellanos was hitting .302 with 17 home runs and 51 RBIs, while playing as the Tigers' starting third baseman.

On August 6, Castellanos was struck by a pitch from New York Mets reliever Logan Verrett, fracturing the fifth metacarpal bone in his left hand.

[37] Castellanos did not return to the Tigers until the final week of the regular season, entering a September 27 game against the Cleveland Indians as a pinch hitter.

[41] Castellanos finished 2017 with a .272 batting average, while setting career highs in doubles (36), triples (10), home runs (26) and RBIs (101).

With the acquisition of third baseman Jeimer Candelario and the departure of right fielder J. D. Martinez, both in July trades, Castellanos began playing games in right field from early September to the end of the 2017 season.

With two singles, two doubles, and a home run, he also became the first Tiger with 10 total bases in a game since Justin Upton in 2017.

[47] He was named the 2018 Tiger of the Year by the Detroit Chapter of the Baseball Writers' Association of America (BBWAA).

[48] On July 31, 2019, the Tigers traded Castellanos along with cash considerations to the Chicago Cubs in exchange for Alex Lange and Paul Richan.

"[51] He also joined Hall of Famers Hank Greenberg (1934) and Joe Medwick (1937) as the only right-handed batters to ever hit 55 doubles and 25 home runs in the same season.

Mid-apology, Castellanos hit a home run, and Brennaman broke from his apology to deliver the play-by-play.

[56] Brennaman said, "I pride myself and think of myself as a man of faith, as there's a drive into deep left field by Castellanos, it will be a home run.

The moment, as well as future instances of Castellanos recording hits during broadcast discussions of negative events, became an internet meme as a copypasta.

"[57] On July 5, 2021, Castellanos hit a home run at Kauffman Stadium while the Kansas City Royals' broadcast was in the middle of a eulogy for a military veteran.

[61][62] Castellanos again interrupted a broadcast moment in a spring training game against the Toronto Blue Jays on March 27, when he recorded his first hit as a Phillie while the Blue Jays broadcast team was discussing the DUI arrest of Toronto pitching coach Pete Walker two days earlier.

[63] On Memorial Day, Castellanos hit a home run just as broadcaster Tom McCarthy had finished telling viewers about the American Gold Star Mothers Chair of Honor in Citizens Bank Park.

However, he went hitless with 11 strikeouts in his final 23 at-bats as the Phillies lost in seven games to the Arizona Diamondbacks despite holding a 2–0 series lead.

[69] Castellanos played in all 162 games for the Phillies in 2024, slashing .254/.311/.431 with 23 home runs, 86 RBI, and six stolen bases.