| 1 | Sun Sep 10 | at Steelers | W30-7 | 1-0 | 1.000 | Acrisure Stadium · Pittsburgh, PA |
| 2 | Sun Sep 17 | at Rams | W30-23 | 2-0 | 1.000 | SoFi Stadium · Inglewood, CA |
| 3 | Thu Sep 21 | vs Giants | W30-12 | 3-0 | 1.000 | Levi's® Stadium · Santa Clara, CA |
| 4 | Sun Oct 1 | vs Cardinals | W35-16 | 4-0 | 1.000 | Levi's® Stadium · Santa Clara, CA |
| 5 | Sun Oct 8 | vs Cowboys | W42-10 | 5-0 | 1.000 | Levi's® Stadium · Santa Clara, CA |
| 6 | Sun Oct 15 | at Browns | L17-19 | 5-1 | .833 | FirstEnergy Stadium · Cleveland, OH |
| 7 | Mon Oct 23 | at Vikings | L17-22 | 5-2 | .714 | U.S. Bank Stadium · Minneapolis, MN |
| 8 | Sun Oct 29 | vs Bengals | L17-31 | 5-3 | .625 | Levi's® Stadium · Santa Clara, CA |
| 9 | -- BYE WEEK -- |
| 10 | Sun Nov 12 | at Jaguars | W34-3 | 6-3 | .667 | TIAA Bank Field · Jacksonville, FL |
| 11 | Sun Nov 19 | vs Buccaneers | W27-14 | 7-3 | .700 | Levi's® Stadium · Santa Clara, CA |
| 12 | Thu Nov 23 | at Seahawks | W31-13 | 8-3 | .727 | Lumen Field · Seattle, WA |
| 13 | Sun Dec 3 | at Eagles | W42-19 | 9-3 | .750 | Lincoln Financial Field · Philadelphia, PA |
| 14 | Sun Dec 10 | vsSeahawks | W28-16 | 10-3 | .769 | Levi's® Stadium · Santa Clara, CA |
| 15 | Sun Dec 17 | atCardinals | W45-29 | 11-3 | .786 | State Farm Stadium · Glendale, AZ |
| 16 | Mon Dec 25 | vs Ravens | L19-33 | 11-4 | .733 | Levi's® Stadium · Santa Clara, CA |
| 17 | Sun Dec 31 | at Commanders | W27-10 | 12-4 | .750 | FedEx Field · North Englewood, MD |
| 18 | Sun Jan 7 | vsRams | L20-21 | 12-5 | .706 | Levi's® Stadium · Santa Clara, CA |
| DIV | Sat Jan 20 | vs Packers | W24-21 | 12-5 | .706 | Levi's® Stadium · Santa Clara, CA |
| CONF | Sun Jan 28 | vs Lions | W34-31 | 12-5 | .706 | Levi's® Stadium · Santa Clara, CA |
| SB | Sun Feb 11 | at Chiefs | L22-25 (OT) | 12-5 | .706 | Allegiant Stadium · Las Vegas, NV |
