| 1 | Sun Sep 13 | at Jaguars | L20-27 | 0-1 | .000 | TIAA Bank Field · Jacksonville, FL |
| 2 | Sun Sep 20 | vsVikings | W28-11 | 1-1 | .500 | Lucas Oil Stadium · Indianapolis, IN |
| 3 | Sun Sep 27 | vsJets | W36-7 | 2-1 | .667 | Lucas Oil Stadium · Indianapolis, IN |
| 4 | Sun Oct 4 | atBears | W19-11 | 3-1 | .750 | Soldier Field · Chicago, IL |
| 5 | Sun Oct 11 | atBrowns | L23-32 | 3-2 | .600 | FirstEnergy Stadium · Cleveland, OH |
| 6 | Sun Oct 18 | vsBengals | W31-27 | 4-2 | .667 | Lucas Oil Stadium · Indianapolis, IN |
| --bye week-- |
| 8 | Sun Nov 1 | atLions | W41-21 | 5-2 | .714 | Ford Field · Detroit, MI |
| 9 | Sun Nov 8 | vsRavens | L10-24 | 5-3 | .625 | Lucas Oil Stadium · Indianapolis, IN |
| 10 | Thu Nov 12 | atTitans | W34-17 | 6-3 | .667 | Nissan Stadium · Nashville, TN |
| 11 | Sun Nov 22 | vsPackers | W34-31 (OT) | 7-3 | .700 | Lucas Oil Stadium · Indianapolis, IN |
| 12 | Sun Nov 29 | vsTitans | L26-45 | 7-4 | .636 | Lucas Oil Stadium · Indianapolis, IN |
| 13 | Sun Dec 6 | atTexans | W26-20 | 8-4 | .667 | NRG Stadium · Houston, TX |
| 14 | Sun Dec 13 | atRaiders | W44-27 | 9-4 | .692 | Allegiant Stadium · Las Vegas, NV |
| 15 | Sun Dec 20 | vsTexans | W27-20 | 10-4 | .714 | Lucas Oil Stadium · Indianapolis, IN |
| 16 | Sun Dec 27 | atSteelers | L24-28 | 10-5 | .667 | Acrisure Stadium · Pittsburgh, PA |
| 17 | Sun Jan 3 | vsJaguars | W28-14 | 11-5 | .688 | Lucas Oil Stadium · Indianapolis, IN |
| WC | Sat Jan 9 | atBills | L24-27 | 11-5 | .688 | Highmark Stadium · Orchard Park, NY |
