| 1 | Sun Sep 12 | vs Seahawks | L16-28 | 0-1 | .000 | Lucas Oil Stadium · Indianapolis, IN |
| 2 | Sun Sep 19 | vsRams | L24-27 | 0-2 | .000 | Lucas Oil Stadium · Indianapolis, IN |
| 3 | Sun Sep 26 | atTitans | L16-25 | 0-3 | .000 | Nissan Stadium · Nashville, TN |
| 4 | Sun Oct 3 | atDolphins | W27-17 | 1-3 | .250 | Hard Rock Stadium · Miami Gardens, FL |
| 5 | Mon Oct 11 | atRavens | L25-31 (OT) | 1-4 | .200 | M&T Bank Stadium · Baltimore, MD |
| 6 | Sun Oct 17 | vsTexans | W31-3 | 2-4 | .333 | Lucas Oil Stadium · Indianapolis, IN |
| 7 | Sun Oct 24 | at49ers | W30-18 | 3-4 | .429 | Levi's® Stadium · Santa Clara, CA |
| 8 | Sun Oct 31 | vsTitans | L31-34 (OT) | 3-5 | .375 | Lucas Oil Stadium · Indianapolis, IN |
| 9 | Thu Nov 4 | vsJets | W45-30 | 4-5 | .444 | Lucas Oil Stadium · Indianapolis, IN |
| 10 | Sun Nov 14 | vsJaguars | W23-17 | 5-5 | .500 | Lucas Oil Stadium · Indianapolis, IN |
| 11 | Sun Nov 21 | atBills | W41-15 | 6-5 | .545 | Highmark Stadium · Orchard Park, NY |
| 12 | Sun Nov 28 | vsBuccaneers | L31-38 | 6-6 | .500 | Lucas Oil Stadium · Indianapolis, IN |
| 13 | Sun Dec 5 | atTexans | W31-0 | 7-6 | .538 | NRG Stadium · Houston, TX |
| --bye week-- |
| 15 | Sat Dec 18 | vsPatriots | W27-17 | 8-6 | .571 | Lucas Oil Stadium · Indianapolis, IN |
| 16 | Sat Dec 25 | atCardinals | W22-16 | 9-6 | .600 | State Farm Stadium · Glendale, AZ |
| 17 | Sun Jan 2 | vsRaiders | L20-23 | 9-7 | .563 | Lucas Oil Stadium · Indianapolis, IN |
| 18 | Sun Jan 9 | atJaguars | L11-26 | 9-8 | .529 | TIAA Bank Field · Jacksonville, FL |
