| 1 | Sun Sep 13 | vs Jets | W27-17 | 1-0 | 1.000 | Highmark Stadium · Orchard Park, NY |
| 2 | Sun Sep 20 | atDolphins | W31-28 | 2-0 | 1.000 | Hard Rock Stadium · Miami Gardens, FL |
| 3 | Sun Sep 27 | vsRams | W35-32 | 3-0 | 1.000 | Highmark Stadium · Orchard Park, NY |
| 4 | Sun Oct 4 | atRaiders | W30-23 | 4-0 | 1.000 | Allegiant Stadium · Las Vegas, NV |
| 5 | Tue Oct 13 | atTitans | L16-42 | 4-1 | .800 | Nissan Stadium · Nashville, TN |
| 6 | Mon Oct 19 | vsChiefs | L17-26 | 4-2 | .667 | Highmark Stadium · Orchard Park, NY |
| 7 | Sun Oct 25 | atJets | W18-10 | 5-2 | .714 | MetLife Stadium · East Rutherford, NJ |
| 8 | Sun Nov 1 | vsPatriots | W24-21 | 6-2 | .750 | Highmark Stadium · Orchard Park, NY |
| 9 | Sun Nov 8 | vsSeahawks | W44-34 | 7-2 | .778 | Highmark Stadium · Orchard Park, NY |
| 10 | Sun Nov 15 | atCardinals | L30-32 | 7-3 | .700 | State Farm Stadium · Glendale, AZ |
| --bye week-- |
| 12 | Sun Nov 29 | vsChargers | W27-17 | 8-3 | .727 | Highmark Stadium · Orchard Park, NY |
| 13 | Mon Dec 7 | at49ers | W34-24 | 9-3 | .750 | State Farm Stadium · Glendale, AZ |
| 14 | Sun Dec 13 | vsSteelers | W26-15 | 10-3 | .769 | Highmark Stadium · Orchard Park, NY |
| 15 | Sat Dec 19 | atBroncos | W48-19 | 11-3 | .786 | Empower Field at Mile High · Denver, CO |
| 16 | Mon Dec 28 | atPatriots | W38-9 | 12-3 | .800 | Gillette Stadium · Foxborough, MA |
| 17 | Sun Jan 3 | vsDolphins | W56-26 | 13-3 | .813 | Highmark Stadium · Orchard Park, NY |
| WC | Sat Jan 9 | vsColts | W27-24 | 13-3 | .813 | Highmark Stadium · Orchard Park, NY |
| DIV | Sat Jan 16 | vsRavens | W17-3 | 13-3 | .813 | Highmark Stadium · Orchard Park, NY |
| CONF | Sun Jan 24 | atChiefs | L24-38 | 13-3 | .813 | Arrowhead Stadium · Kansas City, MO |
