In the season opener, the Colts faced the Jaguars, giving them more than they expected. Despite the strong performance of Anthony Richardson, who passed for 223 yards with a touchdown and an interception, and DeForest Buckner, who returned a fumble for a touchdown, it was not enough to secure a victory. The Jaguars, led by Trevor Lawrence, Calvin Ridley, and Zay Jones, rallied in the fourth quarter, ultimately defeating the Colts 31-21. Lawrence completed 24 of 32 passes for 241 yards with two touchdowns and a pick, while Ridley had eight catches for 101 yards and a touchdown. Jones also made a significant contribution with five receptions for 55 yards and a touchdown.
During the game, the Colts gained a total of 342 yards, with Richardson running for 40 yards on 10 carries. However, his performance was cut short due to an injury sustained during a scramble. Despite their efforts, the Jaguars were able to secure the victory with key plays in the final minutes, including a 1-yard touchdown run by Tank Bigsby and a 26-yard score by Travis Etienne. With only 59 seconds left in the game, Richardson was forced to leave the field due to a hard hit near the goal line, meaning he was unable to participate in the final three snaps.