| W1 | SEP 7, 2025 |  Baltimore RavensBaltimore Ravens @ Buffalo Bills | Home | 40 - 41 | Final | Open |
| W2 | SEP 14, 2025 |  New York JetsBuffalo Bills @ New York Jets | Away | 30 - 10 | Final | Open |
| W3 | SEP 18, 2025 |  Miami DolphinsMiami Dolphins @ Buffalo Bills | Home | 21 - 31 | Final | Open |
| W4 | SEP 28, 2025 |  New Orleans SaintsNew Orleans Saints @ Buffalo Bills | Home | 19 - 31 | Final | Open |
| W5 | OCT 5, 2025 |  New England PatriotsNew England Patriots @ Buffalo Bills | Home | 23 - 20 | Final | Open |
| W6 | OCT 13, 2025 |  Atlanta FalconsBuffalo Bills @ Atlanta Falcons | Away | 14 - 24 | Final | Open |
| W7 | - | ByeBuffalo Bills Bye Week | - | - | Bye | Rest |
| W8 | OCT 26, 2025 |  Carolina PanthersBuffalo Bills @ Carolina Panthers | Away | 40 - 9 | Final | Open |
| W9 | NOV 2, 2025 |  Kansas City ChiefsKansas City Chiefs @ Buffalo Bills | Home | 21 - 28 | Final | Open |
| W10 | NOV 9, 2025 | Miami DolphinsBuffalo Bills @ Miami Dolphins | Away | 13 - 30 | Final | Open |
| W11 | NOV 16, 2025 |  Tampa Bay BuccaneersTampa Bay Buccaneers @ Buffalo Bills | Home | 32 - 44 | Final | Open |
| W12 | NOV 20, 2025 |  Houston TexansBuffalo Bills @ Houston Texans | Away | 19 - 23 | Final | Open |
| W13 | NOV 30, 2025 |  Pittsburgh SteelersBuffalo Bills @ Pittsburgh Steelers | Away | 26 - 7 | Final | Open |
| W14 | DEC 7, 2025 |  Cincinnati BengalsCincinnati Bengals @ Buffalo Bills | Home | 34 - 39 | Final | Open |
| W15 | DEC 14, 2025 | New England PatriotsBuffalo Bills @ New England Patriots | Away | 35 - 31 | Final | Open |
| W16 | DEC 21, 2025 |  Cleveland BrownsBuffalo Bills @ Cleveland Browns | Away | 23 - 20 | Final | Open |
| W17 | DEC 28, 2025 |  Philadelphia EaglesPhiladelphia Eagles @ Buffalo Bills | Home | 13 - 12 | Final | Open |
| W18 | JAN 4, 2026 | New York JetsNew York Jets @ Buffalo Bills | Home | 8 - 35 | Final | Open |
