| 1 | Mon Sep 9 | vs Jets | W32-19 | 1-0 | 1.000 | Levi's® Stadium · Santa Clara, CA |
| 2 | Sun Sep 15 | atVikings | L17-23 | 1-1 | .500 | U.S. Bank Stadium · Minneapolis, MN |
| 3 | Sun Sep 22 | atRams | L24-27 | 1-2 | .333 | SoFi Stadium · Inglewood, CA |
| 4 | Sun Sep 29 | vsPatriots | W30-13 | 2-2 | .500 | Levi's® Stadium · Santa Clara, CA |
| 5 | Sun Oct 6 | vsCardinals | L23-24 | 2-3 | .400 | Levi's® Stadium · Santa Clara, CA |
| 6 | Thu Oct 10 | atSeahawks | W36-24 | 3-3 | .500 | Lumen Field · Seattle, WA |
| 7 | Sun Oct 20 | vsChiefs | L18-28 | 3-4 | .429 | Levi's® Stadium · Santa Clara, CA |
| 8 | Sun Oct 27 | vsCowboys | W30-24 | 4-4 | .500 | Levi's® Stadium · Santa Clara, CA |
| --bye week-- |
| 10 | Sun Nov 10 | atBuccaneers | W23-20 | 5-4 | .556 | Raymond James Stadium · Tampa, FL |
| 11 | Sun Nov 17 | vsSeahawks | L17-20 | 5-5 | .500 | Levi's® Stadium · Santa Clara, CA |
| 12 | Sun Nov 24 | atPackers | L10-38 | 5-6 | .455 | Lambeau Field · Green Bay, WI |
| 13 | Sun Dec 1 | atBills | L10-35 | 5-7 | .417 | Highmark Stadium · Orchard Park, NY |
| 14 | Sun Dec 8 | vsBears | W38-13 | 6-7 | .462 | Levi's® Stadium · Santa Clara, CA |
| 15 | Thu Dec 12 | vsRams | L6-12 | 6-8 | .429 | Levi's® Stadium · Santa Clara, CA |
| 16 | Sun Dec 22 | atDolphins | L17-29 | 6-9 | .400 | Hard Rock Stadium · Miami Gardens, FL |
| 17 | Mon Dec 30 | vsLions | L34-40 | 6-10 | .375 | Levi's® Stadium · Santa Clara, CA |
| 18 | Sun Jan 5 | atCardinals | L24-47 | 6-11 | .353 | State Farm Stadium · Glendale, AZ |
