| 1 | Mon Sep 11 | at Jets | L16-22 (OT) | 0-1 | .000 | MetLife Stadium · East Rutherford, NJ |
| 2 | Sun Sep 17 | vsRaiders | W38-10 | 1-1 | .500 | Highmark Stadium · Orchard Park, NY |
| 3 | Sun Sep 24 | atCommanders | W37-3 | 2-1 | .667 | FedEx Field · North Englewood, MD |
| 4 | Sun Oct 1 | vsDolphins | W48-20 | 3-1 | .750 | Highmark Stadium · Orchard Park, NY |
| 5 | Sun Oct 8 | vsJaguars | L20-25 | 3-2 | .600 | Tottenham Hotspur Stadium · London, England |
| 6 | Sun Oct 15 | vsGiants | W14-9 | 4-2 | .667 | Highmark Stadium · Orchard Park, NY |
| 7 | Sun Oct 22 | atPatriots | L25-29 | 4-3 | .571 | Gillette Stadium · Foxborough, MA |
| 8 | Thu Oct 26 | vsBuccaneers | W24-18 | 5-3 | .625 | Highmark Stadium · Orchard Park, NY |
| 9 | Sun Nov 5 | atBengals | L18-24 | 5-4 | .556 | Paycor Stadium · Cincinnati, OH |
| 10 | Mon Nov 13 | vsBroncos | L22-24 | 5-5 | .500 | Highmark Stadium · Orchard Park, NY |
| 11 | Sun Nov 19 | vsJets | W32-6 | 6-5 | .545 | Highmark Stadium · Orchard Park, NY |
| 12 | Sun Nov 26 | atEagles | L34-37 (OT) | 6-6 | .500 | Lincoln Financial Field · Philadelphia, PA |
| --bye week-- |
| 14 | Sun Dec 10 | atChiefs | W20-17 | 7-6 | .538 | Arrowhead Stadium · Kansas City, MO |
| 15 | Sun Dec 17 | vsCowboys | W31-10 | 8-6 | .571 | Highmark Stadium · Orchard Park, NY |
| 16 | Sat Dec 23 | atChargers | W24-22 | 9-6 | .600 | SoFi Stadium · Inglewood, CA |
| 17 | Sun Dec 31 | vsPatriots | W27-21 | 10-6 | .625 | Highmark Stadium · Orchard Park, NY |
| 18 | Sun Jan 7 | atDolphins | W21-14 | 11-6 | .647 | Hard Rock Stadium · Miami Gardens, FL |
| WC | Mon Jan 15 | vsSteelers | W31-17 | 11-6 | .647 | Highmark Stadium · Orchard Park, NY |
| DIV | Sun Jan 21 | vsChiefs | L24-27 | 11-6 | .647 | Highmark Stadium · Orchard Park, NY |
