| Date | Wk | Side | Opponent | Score | Result | Spread | O/U | Stadium |
|---|---|---|---|---|---|---|---|---|
| 2025-09-07 | 1 | @ | SEA | 17-13 | W | -2.5 | 43.5 | Lumen Field |
| 2025-09-14 | 2 | @ | NO | 26-21 | W | -3 | 40.5 | Mercedes-Benz Superdome |
| 2025-09-21 | 3 | vs | ARI | 16-15 | W | 1.5 | 44.5 | Levi's Stadium |
| 2025-09-28 | 4 | vs | JAX | 21-26 | L | 3.5 | 45.5 | Levi's Stadium |
| 2025-10-02 | 5 | @ | LA | 26-23 | W | 8.5 | 43.5 | SoFi Stadium |
| 2025-10-12 | 6 | @ | TB | 19-30 | L | 3.5 | 46.5 | Raymond James Stadium |
| 2025-10-19 | 7 | vs | ATL | 20-10 | W | 1.5 | 46.5 | Levi's Stadium |
| 2025-10-26 | 8 | @ | HOU | 15-26 | L | 2.5 | 41.5 | NRG Stadium |
| 2025-11-02 | 9 | @ | NYG | 34-24 | W | -2.5 | 47.5 | MetLife Stadium |
| 2025-11-09 | 10 | vs | LA | 26-42 | L | -5.5 | 49.5 | Levi's Stadium |
| 2025-11-16 | 11 | @ | ARI | 41-22 | W | -3.5 | 48.5 | State Farm Stadium |
| 2025-11-24 | 12 | vs | CAR | 20-9 | W | 7.5 | 48.5 | Levi's Stadium |
| 2025-11-30 | 13 | @ | CLE | 26-8 | W | -5.5 | 35.5 | FirstEnergy Stadium |
| 2025-12-14 | 15 | vs | TEN | 37-24 | W | 12.5 | 44.5 | Levi's Stadium |
| 2025-12-22 | 16 | @ | IND | 48-27 | W | -4.5 | 46.5 | Lucas Oil Stadium |
| 2025-12-28 | 17 | vs | CHI | 42-38 | W | 3.5 | 51.5 | Levi's Stadium |
| 2026-01-03 | 18 | vs | SEA | 3-13 | L | -2.5 | 47.5 | Levi's Stadium |
| 2026-01-11 | 19 | @ | PHI | 23-19 | W | 6 | 44.5 | Lincoln Financial Field |
| 2026-01-17 | 20 | @ | SEA | 6-41 | L | 6.5 | 44.5 | Lumen Field |
