| 1 | Sun Sep 10 | vs Jaguars | L21-31 | 0-1 | .000 | Lucas Oil Stadium · Indianapolis, IN |
| 2 | Sun Sep 17 | atTexans | W31-20 | 1-1 | .500 | NRG Stadium · Houston, TX |
| 3 | Sun Sep 24 | atRavens | W22-19 (OT) | 2-1 | .667 | M&T Bank Stadium · Baltimore, MD |
| 4 | Sun Oct 1 | vsRams | L23-29 (OT) | 2-2 | .500 | Lucas Oil Stadium · Indianapolis, IN |
| 5 | Sun Oct 8 | vsTitans | W23-16 | 3-2 | .600 | Lucas Oil Stadium · Indianapolis, IN |
| 6 | Sun Oct 15 | atJaguars | L20-37 | 3-3 | .500 | TIAA Bank Field · Jacksonville, FL |
| 7 | Sun Oct 22 | vsBrowns | L38-39 | 3-4 | .429 | Lucas Oil Stadium · Indianapolis, IN |
| 8 | Sun Oct 29 | vsSaints | L27-38 | 3-5 | .375 | Lucas Oil Stadium · Indianapolis, IN |
| 9 | Sun Nov 5 | atPanthers | W27-13 | 4-5 | .444 | Bank of America Stadium · Charlotte, NC |
| 10 | Sun Nov 12 | atPatriots | W10-6 | 5-5 | .500 | Deutsche Bank Park · Frankfurt, Germany |
| --bye week-- |
| 12 | Sun Nov 26 | vsBuccaneers | W27-20 | 6-5 | .545 | Lucas Oil Stadium · Indianapolis, IN |
| 13 | Sun Dec 3 | atTitans | W31-28 (OT) | 7-5 | .583 | Nissan Stadium · Nashville, TN |
| 14 | Sun Dec 10 | atBengals | L14-34 | 7-6 | .538 | Paycor Stadium · Cincinnati, OH |
| 15 | Sat Dec 16 | vsSteelers | W30-13 | 8-6 | .571 | Lucas Oil Stadium · Indianapolis, IN |
| 16 | Sun Dec 24 | atFalcons | L10-29 | 8-7 | .533 | Mercedes-Benz Stadium · Atlanta, GA |
| 17 | Sun Dec 31 | vsRaiders | W23-20 | 9-7 | .563 | Lucas Oil Stadium · Indianapolis, IN |
| 18 | Sat Jan 6 | vsTexans | L19-23 | 9-8 | .529 | Lucas Oil Stadium · Indianapolis, IN |
