| 1 | Sun Sep 7 | at Seahawks | W17-13 | 1-0 | 1.000 | Lumen Field · Seattle, WA |
| 2 | Sun Sep 14 | atSaints | W26-21 | 2-0 | 1.000 | Caesars Superdome · New Orleans, LA |
| 3 | Sun Sep 21 | vsCardinals | W16-15 | 3-0 | 1.000 | Levi's® Stadium · Santa Clara, CA |
| 4 | Sun Sep 28 | vsJaguars | L21-26 | 3-1 | .750 | Levi's® Stadium · Santa Clara, CA |
| 5 | Thu Oct 2 | atRams | W26-23 (OT) | 4-1 | .800 | SoFi Stadium · Inglewood, CA |
| 6 | Sun Oct 12 | atBuccaneers | L19-30 | 4-2 | .667 | Raymond James Stadium · Tampa, FL |
| 7 | Sun Oct 19 | vsFalcons | W20-10 | 5-2 | .714 | Levi's® Stadium · Santa Clara, CA |
| 8 | Sun Oct 26 | atTexans | L15-26 | 5-3 | .625 | NRG Stadium · Houston, TX |
| 9 | Sun Nov 2 | atGiants | W34-24 | 6-3 | .667 | MetLife Stadium · East Rutherford, NJ |
| 10 | Sun Nov 9 | vsRams | L26-42 | 6-4 | .600 | Levi's® Stadium · Santa Clara, CA |
| 11 | Sun Nov 16 | atCardinals | W41-22 | 7-4 | .636 | State Farm Stadium · Glendale, AZ |
| 12 | Mon Nov 24 | vsPanthers | W20-9 | 8-4 | .667 | Levi's® Stadium · Santa Clara, CA |
| 13 | Sun Nov 30 | atBrowns | W26-8 | 9-4 | .692 | FirstEnergy Stadium · Cleveland, OH |
| --bye week-- |
| 15 | Sun Dec 14 | vsTitans | W37-24 | 10-4 | .714 | Levi's® Stadium · Santa Clara, CA |
| 16 | Mon Dec 22 | atColts | W48-27 | 11-4 | .733 | Lucas Oil Stadium · Indianapolis, IN |
| 17 | Sun Dec 28 | vsBears | W42-38 | 12-4 | .750 | Levi's® Stadium · Santa Clara, CA |
| 18 | Sat Jan 3 | vsSeahawks | L3-13 | 12-5 | .706 | Levi's® Stadium · Santa Clara, CA |
| WC | Sun Jan 11 | atEagles | W23-19 | 12-5 | .706 | Lincoln Financial Field · Philadelphia, PA |
| DIV | Sat Jan 17 | atSeahawks | L6-41 | 12-5 | .706 | Lumen Field · Seattle, WA |
