Murray played his first NFL game on September 8, 2019 against the Detroit Lions, finishing with 308 passing yards, two touchdowns, and an interception as the game ended in a 27–all tie. Murray led the Cardinals to a comeback in the fourth quarter from a 16-point deficit, joining Jake Plummer as the only Cardinals rookie quarterbacks to throw for 300 yards and two touchdowns since the AFL-NFL merger in 1970. During Week 2 against the Baltimore Ravens, Murray finished with 349 passing yards as the Cardinals lost 17–23. In Week 4 against the Seattle Seahawks, Murray threw for 241 yards and a pick-six and rushed four times for 27 yards and his first NFL rushing touchdown in the 27–10 loss. In the next game against the Cincinnati Bengals, Murray threw for 253 yards and rushed for 93 yards and a touchdown in the 26–23 victory. During Week 6 against the Atlanta Falcons, Murray threw for 340 yards and three touchdowns and rushed 11 times for 32 yards in a narrow 34–33 victory.  He was named the NFC Offensive Player of the Week for his performance.  In Week 10, against the Tampa Bay Buccaneers, he had 324 passing yards, three touchdowns, and one interception in the 30–27 loss.  In Week 11 against the San Francisco 49ers, Murray threw for 150 yards and two touchdowns and rushed for 67 yards and a touchdown in the 36–26 loss.  In Week 16 against the Seattle Seahawks, Murray threw for 118 yards and a touchdown and rushed for 40 yards before exiting the game due to a hamstring injury. Without Murray, the Cardinals won the game 27–13.  Before the regular season finale against the Los Angeles Rams, Murray was listed as a game time decision with a hamstring injury and ultimately played in the game despite being hurt. During the game, Murray threw for 325 yards, two touchdowns, and two interceptions during the 31–24 loss. Afterwards, Cardinals' head coach Kliff Kingsbury said that "It's the most proud I've been of him all season. "