The Detroit Tigers selected Holaday in the sixth round of the 2010 Major League Baseball Draft. He signed, and played for the Lakeland Tigers of the Class A-AdvancedFlorida State League that season. He attended Tigers' spring training as a non-roster invitee in 2011. He played for the Erie SeaWolves of the Eastern League, the Tigers Class AA affiliate, during the 2011 season. He was again invited to spring training as a non-roster invitee in 2012. He started the season with the Toledo Mud Hens of the Class AAAInternational League, where he batted.248 with no home runs and ten RBIs. in 2013 The Tigers promoted Holaday to the major leagues on June 6, 2012, as the team added him to their 40-man roster due to injuries to starting catcher Alex Avila. He became the third position player selected in the 2010 draft to reach the majors, following Bryce Harper and Kole Calhoun. Holaday made his MLB debut that day. He had one hit in four at bats during his debut. Holaday was recalled June 17, 2013, when catcher Alex Avila was placed on the disabled list. For the season he batted.296/.367/.444. After the 2013 season, the Tigers informed backup catcher Brayan Peña they would not re-sign him, giving Holaday the opportunity to become the backup to Avila. Holaday competed with James McCann to be the backup catcher behind Avila during spring training in 2015. McCann won the competition, and Holaday began the season in the minor leagues. For the season in the majors, he batted.281/.292/.453. Once again, Holaday entered spring training in 2016 competing for a backup role, this time with Jarrod Saltalamacchia. Despite losing the job, Holaday attracted large amounts of trade interest due to hitting.438/.455/.969 in 16 games and his lack of minor league options remaining. In 4 seasons with the Tigers, Holaday hit.251/.283/.340 with 3 HR and 30 RBI in 108 games.
On December 20, 2016, Holaday signed a minor league deal with the Philadelphia Phillies. After being informed that he would not make Philadelphia's roster to begin the season, Holaday opted out of his contract.
Return to Detroit
On March 31, 2017, the Tigers signed Holaday to a minor league contract and assigned him to the Toledo Mud Hens. On September 1, the Tigers purchased Holaday's contract. At the time of his call-up, Holaday was hitting.269 with 12 home runs and 50 RBI in 93 games for Toledo. He was outrighted to Triple-A on November 3, and elected free agency on November 7.
Miami Marlins
On December 1, 2017, Holaday signed a minor league contract with the Miami Marlins. Holaday's contract was purchased by the Marlins on March 28, 2018, and he was assigned to the Opening Day roster. He elected free agency on October 27. On November 26, Holaday re-signed with the Marlins to a minor league contract. He was released on March 23, 2019, after opting out of his contract. However, he re-signed to another minor league deal on March 26 to stay with the Marlins. He opened the 2019 season with the New Orleans Baby Cakes. Following the 2019 season, Holaday was outrighted off the Marlins roster and elected free agency on October 18.
Baltimore Orioles
On January 13, 2020, Holaday signed a minor league deal with the Baltimore Orioles that included an invitation to spring training.