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. After a Week 6 loss to the New Orleans Saints and a Week 7 victory over the Cincinnati Bengals, he had 279 passing yards and three passing touchdowns in a 29–15 victory over the New York Jets. During Week 9 against the Texans at Wembley Stadium, Minshew finished with 309 passing yards and 2 interceptions as the Jaguars lost 3–26. Days later, it was announced that Minshew would resume the backup role after Foles returned from his collar bone injury. In week 13 against the Tampa Bay Buccaneers, Minshew was reinserted into the starting lineup in the second half after Foles was benched due to poor performance. In the game, Minshew threw for 147 yards, one touchdown, and one interception in the 28–11 loss. After the game, Jaguars' head coach Doug Marrone stated that Minshew would be the starting quarterback for the upcoming game. In Week 15 against the Oakland Raiders, Minshew threw for 201 yards and two touchdowns to wide receiver Chris Conley, both of which occurred with five or less minutes in the game, as the Jaguars recovered from a 16–3 deficit to win the game 20–16. In Week 17 against the Indianapolis Colts, Minshew threw for 295 yards, three touchdowns, and one interception during the 38–20 win. Overall, he appeared in 14 games and recorded 3,271 passing yards, 21 passing touchdowns, and six interceptions to go along with 67 carries for 344 rushing yards in his rookie season.