| 1 | Sun Sep 7 | vs Ravens | W41-40 | 1-0 | 1.000 | Highmark Stadium · Orchard Park, NY |
| 2 | Sun Sep 14 | atJets | W30-10 | 2-0 | 1.000 | MetLife Stadium · East Rutherford, NJ |
| 3 | Thu Sep 18 | vsDolphins | W31-21 | 3-0 | 1.000 | Highmark Stadium · Orchard Park, NY |
| 4 | Sun Sep 28 | vsSaints | W31-19 | 4-0 | 1.000 | Highmark Stadium · Orchard Park, NY |
| 5 | Sun Oct 5 | vsPatriots | L20-23 | 4-1 | .800 | Highmark Stadium · Orchard Park, NY |
| 6 | Mon Oct 13 | atFalcons | L14-24 | 4-2 | .667 | Mercedes-Benz Stadium · Atlanta, GA |
| --bye week-- |
| 8 | Sun Oct 26 | atPanthers | W40-9 | 5-2 | .714 | Bank of America Stadium · Charlotte, NC |
| 9 | Sun Nov 2 | vsChiefs | W28-21 | 6-2 | .750 | Highmark Stadium · Orchard Park, NY |
| 10 | Sun Nov 9 | atDolphins | L13-30 | 6-3 | .667 | Hard Rock Stadium · Miami Gardens, FL |
| 11 | Sun Nov 16 | vsBuccaneers | W44-32 | 7-3 | .700 | Highmark Stadium · Orchard Park, NY |
| 12 | Thu Nov 20 | atTexans | L19-23 | 7-4 | .636 | NRG Stadium · Houston, TX |
| 13 | Sun Nov 30 | atSteelers | W26-7 | 8-4 | .667 | Acrisure Stadium · Pittsburgh, PA |
| 14 | Sun Dec 7 | vsBengals | W39-34 | 9-4 | .692 | Highmark Stadium · Orchard Park, NY |
| 15 | Sun Dec 14 | atPatriots | W35-31 | 10-4 | .714 | Gillette Stadium · Foxborough, MA |
| 16 | Sun Dec 21 | atBrowns | W23-20 | 11-4 | .733 | FirstEnergy Stadium · Cleveland, OH |
| 17 | Sun Dec 28 | vsEagles | L12-13 | 11-5 | .688 | Highmark Stadium · Orchard Park, NY |
| 18 | Sun Jan 4 | vsJets | W35-8 | 12-5 | .706 | Highmark Stadium · Orchard Park, NY |
| WC | Sun Jan 11 | atJaguars | W27-24 | 12-5 | .706 | TIAA Bank Field · Jacksonville, FL |
| DIV | Sat Jan 17 | atBroncos | L30-33 (OT) | 12-5 | .706 | Empower Field at Mile High · Denver, CO |
