| 1 | Sun Sep 11 | at Texans | T20-20 (OT) | 0-0-1 | .000 | NRG Stadium · Houston, TX |
| 2 | Sun Sep 18 | atJaguars | L0-24 | 0-1-1 | .000 | TIAA Bank Field · Jacksonville, FL |
| 3 | Sun Sep 25 | vsChiefs | W20-17 | 1-1-1 | .500 | Lucas Oil Stadium · Indianapolis, IN |
| 4 | Sun Oct 2 | vsTitans | L17-24 | 1-2-1 | .333 | Lucas Oil Stadium · Indianapolis, IN |
| 5 | Thu Oct 6 | atBroncos | W12-9 (OT) | 2-2-1 | .500 | Empower Field at Mile High · Denver, CO |
| 6 | Sun Oct 16 | vsJaguars | W34-27 | 3-2-1 | .600 | Lucas Oil Stadium · Indianapolis, IN |
| 7 | Sun Oct 23 | atTitans | L10-19 | 3-3-1 | .500 | Nissan Stadium · Nashville, TN |
| 8 | Sun Oct 30 | vsCommanders | L16-17 | 3-4-1 | .429 | Lucas Oil Stadium · Indianapolis, IN |
| 9 | Sun Nov 6 | atPatriots | L3-26 | 3-5-1 | .375 | Gillette Stadium · Foxborough, MA |
| 10 | Sun Nov 13 | atRaiders | W25-20 | 4-5-1 | .444 | Allegiant Stadium · Las Vegas, NV |
| 11 | Sun Nov 20 | vsEagles | L16-17 | 4-6-1 | .400 | Lucas Oil Stadium · Indianapolis, IN |
| 12 | Mon Nov 28 | vsSteelers | L17-24 | 4-7-1 | .364 | Lucas Oil Stadium · Indianapolis, IN |
| 13 | Sun Dec 4 | atCowboys | L19-54 | 4-8-1 | .333 | AT&T Stadium · Arlington, TX |
| --bye week-- |
| 15 | Sat Dec 17 | atVikings | L36-39 (OT) | 4-9-1 | .308 | U.S. Bank Stadium · Minneapolis, MN |
| 16 | Mon Dec 26 | vsChargers | L3-20 | 4-10-1 | .286 | Lucas Oil Stadium · Indianapolis, IN |
| 17 | Sun Jan 1 | atGiants | L10-38 | 4-11-1 | .267 | MetLife Stadium · East Rutherford, NJ |
| 18 | Sun Jan 8 | vsTexans | L31-32 | 4-12-1 | .250 | Lucas Oil Stadium · Indianapolis, IN |
