In 2019, the Tigers invited Mize to spring training as a non-roster player.[15] He returned to Lakeland to begin the 2019 season, and was its Opening Day starter.[16] After making four starts for Lakeland with an 0.35 ERA, the Tigers promoted Mize to the Erie SeaWolves of the Double–AEastern League.[17] In his first start for Erie, he tossed a no-hitter, in which he hit a batter, walked another, and struck out seven on 98 pitches, in a 1–0 SeaWolves victory over the Altoona Curve.[18] On June 15, Mize was placed on the 7-day injured list with shoulder inflammation.[19]
Detroit Tigers
2020
On August 19, 2020, Mize was promoted to the major leagues by the Tigers and made his MLB debut that evening against the Chicago White Sox.[20][21][22] Mize threw 73 pitches over 4+1⁄3 innings in his first start, allowing three earned runs while striking out seven and walking none in a no-decision.[23] On September 11 against the Chicago White Sox, Mize took a no-hitter into the sixth inning, before a double by Yolmer Sánchez ruined the no-hit bid.[24] With the 2020 Detroit Tigers, Mize appeared in seven games, compiling a 0–3 record with 6.99 ERA and 26 strikeouts in 28+1⁄3 innings pitched.[25]
2021
On March 26, 2021, Tigers manager A. J. Hinch announced that Mize would be in the Tigers starting rotation to begin the 2021 season.[26] On April 12, Mize earned his first major league win, throwing seven scoreless innings in the Tigers' 6–2 victory over the Houston Astros.[27] In an August 24 road game against the St. Louis Cardinals, Mize made his major league debut as a batter, and collected an RBI on a bases-loaded walk. He also earned the win with five scoreless innings.[28] Mize made 30 starts in the 2021 season, posting a 7–9 record and 3.71 ERA. He struck out 118 batters in 150+1⁄3 innings, while allowing 130 hits and 41 walks for a 1.137 WHIP.
2022
Mize began the 2022 season as the No. 2 starter in the Tigers rotation. On April 15, the Tigers placed Mize on the 10-day injured list with a right elbow sprain.[29] On June 10, he went on the Tigers' 60-day Injured List. It was revealed that Mize needed Tommy John surgery, which prematurely ended his 2022 season.
2023
Mize did not pitch in a professional game in 2023 as he continued his recovery from Tommy John surgery.
2024
Entering the 2024 season, Mize made the Tigers' Opening Day roster as part of their rotation, beating out Matt Manning for one of the final spots. He was named the team's number five starter.[30] Mize made his first 16 starts of the 2024 season before being placed on the 15-day injured list with a left hamstring strain on July 3.[31] He was transferred to the 60–day injured list on July 29.[32] Mize was activated on August 30.[33]