| Week 1 | Baltimore Ravens vs. Buffalo Bills | Sunday, September 7th, 2025 at 8:20pm ET |
| Week 2 | Buffalo Bills vs. New York Jets | Sunday, September 14th, 2025 at 1:00pm ET |
| Week 3 | Miami Dolphins vs. Buffalo Bills | Thursday, September 18th, 2025 at 8:15pm ET |
| Week 4 | New Orleans Saints vs. Buffalo Bills | Sunday, September 28th, 2025 at 1:00pm ET |
| Week 5 | New England Patriots vs. Buffalo Bills | Sunday, October 5th, 2025 at 8:20pm ET |
| Week 6 | Buffalo Bills vs. Atlanta Falcons | Monday, October 13th, 2025 at 7:15pm ET |
| Week 7 | Bye Week | |
| Week 8 | Buffalo Bills vs. Carolina Panthers | Sunday, October 26th, 2025 at 1:00pm ET |
| Week 9 | Kansas City Chiefs vs. Buffalo Bills | Sunday, November 2nd, 2025 at 4:25pm ET |
| Week 10 | Buffalo Bills vs. Miami Dolphins | Sunday, November 9th, 2025 at 1:00pm ET |
| Week 11 | Tampa Bay Buccaneers vs. Buffalo Bills | Sunday, November 16th, 2025 at 1:00pm ET |
| Week 12 | Buffalo Bills vs. Houston Texans | Thursday, November 20th, 2025 at 8:15pm ET |
| Week 13 | Buffalo Bills vs. Pittsburgh Steelers | Sunday, November 30th, 2025 at 4:25pm ET |
| Week 14 | Cincinnati Bengals vs. Buffalo Bills | Sunday, December 7th, 2025 at 1:00pm ET |
| Week 15 | Buffalo Bills vs. New England Patriots | Sunday, December 14th, 2025 at 1:00pm ET |
| Week 16 | Buffalo Bills vs. Cleveland Browns | Sunday, December 21st, 2025 at 1:00pm ET |
| Week 17 | Philadelphia Eagles vs. Buffalo Bills | Sunday, December 28th, 2025 at 4:25pm ET |
| Week 18 | New York Jets vs. Buffalo Bills | Sunday, January 4th, 2026 at 1:00pm ET |
