| 1 | Sun Sep 12 | at Lions | W41-33 | 1-0 | 1.000 | Ford Field · Detroit, MI |
| 2 | Sun Sep 19 | at Eagles | W17-11 | 2-0 | 1.000 | Lincoln Financial Field · Philadelphia, PA |
| 3 | Sun Sep 26 | vs Packers | L28-30 | 2-1 | .667 | Levi's® Stadium · Santa Clara, CA |
| 4 | Sun Oct 3 | vs Seahawks | L21-28 | 2-2 | .500 | Levi's® Stadium · Santa Clara, CA |
| 5 | Sun Oct 10 | at Cardinals | L10-17 | 2-3 | .400 | State Farm Stadium · Glendale, AZ |
| 6 | -- BYE WEEK -- |
| 7 | Sun Oct 24 | vs Colts | L18-30 | 2-4 | .333 | Levi's® Stadium · Santa Clara, CA |
| 8 | Sun Oct 31 | at Bears | W33-22 | 3-4 | .429 | Soldier Field · Chicago, IL |
| 9 | Sun Nov 7 | vsCardinals | L17-31 | 3-5 | .375 | Levi's® Stadium · Santa Clara, CA |
| 10 | Mon Nov 15 | vs Rams | W31-10 | 4-5 | .444 | Levi's® Stadium · Santa Clara, CA |
| 11 | Sun Nov 21 | at Jaguars | W30-10 | 5-5 | .500 | TIAA Bank Field · Jacksonville, FL |
| 12 | Sun Nov 28 | vs Vikings | W34-26 | 6-5 | .545 | Levi's® Stadium · Santa Clara, CA |
| 13 | Sun Dec 5 | atSeahawks | L23-30 | 6-6 | .500 | Lumen Field · Seattle, WA |
| 14 | Sun Dec 12 | at Bengals | W26-23 (OT) | 7-6 | .538 | Paycor Stadium · Cincinnati, OH |
| 15 | Sun Dec 19 | vs Falcons | W31-13 | 8-6 | .571 | Levi's® Stadium · Santa Clara, CA |
| 16 | Thu Dec 23 | at Titans | L17-20 | 8-7 | .533 | Nissan Stadium · Nashville, TN |
| 17 | Sun Jan 2 | vs Texans | W23-7 | 9-7 | .563 | Levi's® Stadium · Santa Clara, CA |
| 18 | Sun Jan 9 | atRams | W27-24 (OT) | 10-7 | .588 | SoFi Stadium · Inglewood, CA |
| WC | Sun Jan 16 | at Cowboys | W23-17 | 10-7 | .588 | AT&T Stadium · Arlington, TX |
| DIV | Sat Jan 22 | atPackers | W13-10 | 10-7 | .588 | Lambeau Field · Green Bay, WI |
| CONF | Sun Jan 30 | atRams | L17-20 | 10-7 | .588 | SoFi Stadium · Inglewood, CA |
