Ryan was ruled out with an ankle injury in Week 8 against the Seattle Seahawks, ending Ryan's streak of 154 consecutive regular season games started. The streak was fifth all-time for quarterbacks. Ryan returned from injury in Week 10 against the New Orleans Saints and threw for 182 yards, two touchdowns, and one interception in the 26–9 upset win. In Week 11 against the Carolina Panthers, Ryan threw for 311 yards and a touchdown in the 29–3 win. In the game, Ryan surpassed Warren Moon for the 10th all time passing yards in NFL history. In Week 13 against the Carolina Panthers, Ryan threw for 313 yards and two touchdowns, including a career long 93-yard touchdown to Olamide Zaccheaus in the 40–20 win. In the game, Ryan became the 10th quarterback in NFL history to reach 50,000 career passing yards. In Week 15, against the heavily-favored San Francisco 49ers, Ryan helped lead a 29–22 upset victory. In the last moments of the game, Ryan threw a five-yard pass to Julio Jones to go ahead before a defensive score put the game away for good. In Week 16, against the Jacksonville Jaguars, Ryan passed for 384 yards, one touchdown, and two interceptions in the 24–12 victory. In Week 17 against the Tampa Bay Buccaneers, Ryan threw for 313 yards and a touchdown during the 28–22 overtime win. Ryan finished the 2019 season with 4,466 passing yards, 26 touchdowns, and 14 interceptions as the Falcons finished with a 7–9 record.