On September 8, 2019, Minshew made his NFL debut against the Kansas City Chiefs when starter Nick Foles was taken out of the game due to a shoulder injury. He completed 22 of 25 passes for 275 yards, two touchdowns and an interception in the 40–26 loss. Minshew's pass completion percentage of 88% is the highest of any player making his debut in NFL history (minimum 15 pass attempts, since at least 1950), and also the highest single-game pass completion percentage in Jaguars history. Minshew was named the starter going forward after it was revealed that Foles had suffered a broken clavicle. During Week 2 against the Houston Texans, Minshew finished with 213 passing yards and a touchdown along with 56 rushing yards as the Jaguars lost 13–12. In Week 3, against the Tennessee Titans on Thursday Night Football, he earned his first victory as a professional. He passed for 204 yards and two touchdowns in the 20–7 victory. In Week 4, against the Denver Broncos, he passed for 213 yards and two touchdowns in the 26–24 victory. Late in the game, he engineered a drive that helped set up the Jaguars' game-winning field goal by Josh Lambo. During Week 5 against the Carolina Panthers, Minshew finished with 374 passing yards and two touchdowns as the Jaguars lost 27–34.