On September 29, Castellanos recorded his 100th RBI of the season. Castellanos became the 10th player in Tigers history to drive in more than 100 runs at the age of 25 or younger, and the first player to do so since Miguel Cabrera in 2008. He became the sixth player in Tigers history to record 10 or more triples, 25 or more home runs and 100 or more RBIs in a season, and the first player to do so since Al Kaline in 1956. Castellanos finished 2017 with a .272 batting average, while setting career highs in doubles (36), triples (10), home runs (26) and RBI (101). His 10 triples led the American League.

Castellanos was raised by his parents, Michelle and Jorge, in South Florida. His mother’s family is based in Michigan. Castellanos attended the American Heritage School in Plantation, Florida, where he played for the school’s baseball team. American Heritage won the Florida state championship in his sophomore year. Castellanos transferred to Archbishop McCarthy High School in Fort Lauderdale, Florida, before his junior year. He was named Gatorade Player of the Year for the state of Florida after finishing his senior season with a .542 batting average, 34 runs scored, 41 runs batted in (RBIs) and 22 stolen bases while leading his team to the Class 4A state championship. 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. The Sun-Sentinel named Castellanos the Class 6A-5A-4A Player of the Year.

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. Castellanos was named to the All-Tournament team. He committed to attend the University of Miami on a baseball scholarship. He intended to play college baseball for the Miami Hurricanes baseball team in the Atlantic Coast Conference.

The Detroit Tigers selected Castellanos with the 44th pick in the 2010 Major League Baseball draft. He was rated by Baseball America as the third best power hitting prospect and fourteenth best overall prospect prior to the draft. He slipped because of his commitment to the University of Miami. He signed with the Tigers, receiving a $3.45 million signing bonus, the highest bonus at that point ever given to a player taken after the first round. The deal was almost invalidated, as the Tigers’ email to the office of the Commissioner of Baseball was not received until three minutes after the midnight deadline on August 15, 2010; a text message about the deal to the Commissioner’s Office received at 11:59 convinced the Commissioner to approve the deal.

Prior to the 2012 season, Baseball America ranked him as the second best prospect in the organization and 45th best in baseball. The Tigers invited Castellanos to spring training in 2012, and expect to assign him to either the Class-A Advanced Lakeland Tigers of the Florida State League or the Class-AA Erie SeaWolves of the Eastern League. Castellanos began the 2012 season with Class-A Lakeland. He was named the Tigers’ minor league player of the month of May 2012. After he batted .402 with 32 RBIs in 55 games for Lakeland, the Tigers promoted Castellanos to Erie on June 4. Appearing in the 2012 All-Star Futures Game, Castellanos hit a three-run home run, and was named the game’s Most Valuable Player. He batted .264 with Erie that year.

When major league rosters expanded on September 1, 2013, Castellanos was among the players promoted to the Tigers, and made his major league debut that day, playing left field. On September 7, Castellanos made his first major league start, and recorded his first major league hit, an infield single, off Danny Duffy. 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. He batted 5-for-18 with the Tigers in 2013.

After the 2013 season, the Tigers traded Prince Fielder. 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.

Castellanos has a son named Liam born in August 2013. He married Vanessa Hernandez, Liam’s mother, in 2015. They divorced in 2016.

Castellanos hit his first MLB home run on April 9, 2014 off the top of the wall in dead center field off Josh Beckett of the Los Angeles Dodgers at Dodger Stadium. He finished his rookie season with a .259 batting average, 11 home runs, 31 doubles and 66 RBIs. He was named the 2014 Detroit Tigers/Detroit Sports Broadcasters Association Rookie of the Year.

On July 22, 2015, Castellanos hit his first career grand slam off Mike Montgomery of the Seattle Mariners. Castellanos hit .255 this season, while slamming 15 home runs and driving in 73.

On January 13, 2017, the Tigers avoided arbitration with Castellanos, agreeing on a one-year contract worth $3 million. On July 18, Castellanos hit a single, triple and two home runs in a game against the Kansas City Royals, becoming the fourth Tigers player to do so since 1913, and the first Tigers player to do so since Dmitri Young in 2003. 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.

Castellanos’ younger brother, Ryan, played college baseball for Nova Southeastern University and was drafted by the Tigers in the 25th round of the 2015 Major League Baseball Draft. In 2017, his father was diagnosed with brain cancer.

On January 17, 2018, the Tigers avoided arbitration with Castellanos, agreeing on a one-year contract worth $6.05 million. On August 13, Castellanos went 5-for-5 with 5 RBIs, for his first career five-hit game. He became the first Tigers player with five hits in a game since Ian Kinsler in 2015. 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. Castellanos earned American League Player of the Week honors for the week of August 13–19. In seven games, he batted .393 with an OBP of .485, and had two homers, three doubles, eight runs scored and ten RBI. The award was the first weekly honor for any Tiger player in 2018, and the first since J.D. Martinez won the award for the week ending July 17, 2017.

Castellanos hit a career-high .298 in the 2018 season, adding 23 home runs and 89 RBI. He finished among the AL leaders in hits (185, third), doubles (46, fourth) and multi-hit games (56, third). He also led all MLB hitters (60 or more plate appearances) in batting average against left-handers, at .381. He was named the 2018 Tiger of the Year by the Detroit Chapter of the Baseball Writers Association of America (BBWAA).

On January 11, 2019, the Tigers avoided arbitration with Castellanos, agreeing on a one-year contract worth $9.95 million.

On July 31, 2019, the Tigers traded Castellanos along with cash considerations to the Chicago Cubs in exchange for Alex Lange and Paul Richan. In the month of August, Castellanos hit .348 with 11 homers, 20 RBIs, and 9 doubles to go along with a .385 on-base percentage and a .713 slugging percentage. In 51 games for the Cubs in 2019, Castellanos hit .321 with 16 home runs, 36 RBI, and a 1.002 OPS.

On defense in 2019, he had a −9 Defensive Runs Saved (DRS) rating, the lowest in the major leagues among right fielders.

On January 27, 2020, Castellanos signed a 4-year $64 million dollar contract with the Cincinnati Reds.

On defense in 2020, he had a fielding percentage of .963, the lowest among all major league right fielders.