| Sep 12 SF @ SEA | 4:15 PM | |
| Sep 20 NO @ SF | 8:30 PM | |
| Sep 26 SF @ KC | 1:00 PM | |
| Oct 03 SF @ ATL | 1:00 PM | |
| Oct 10 PHI @ SF | 8:20 PM | |
| Oct 17 OAK @ SF | 4:05 PM | |
| Oct 24 SF @ CAR | 1:00 PM | |
| Oct 31 DEN @ SF | 1:00 PM | |
| Bye | - | |
| Nov 14 STL @ SF | 4:15 PM | |
| Nov 21 TB @ SF | 4:05 PM | |
| Nov 29 SF @ ARI | 8:30 PM | |
| Dec 05 SF @ GB | 1:00 PM | |
| Dec 12 SEA @ SF | 4:05 PM | |
| Dec 16 SF @ SD | 8:20 PM | |
| Dec 26 SF @ STL | 1:00 PM | |
| Jan 02 ARI @ SF | 4:15 PM | |
| Sep 13 SF @ ARI | W 20-16 (1-0) | |
| Sep 20 SEA @ SF | W 23-10 (2-0) | |
| Sep 27 SF @ MIN | L 24-27 (2-1) | |
| Oct 04 STL @ SF | W 35-0 (3-1) | |
| Oct 11 ATL @ SF | L 10-45 (3-2) | |
| Bye | Bye | |
| Oct 25 SF @ HOU | L 21-24 (3-3) | |
| Nov 01 SF @ IND | L 14-18 (3-4) | |
| Nov 08 TEN @ SF | L 27-34 (3-5) | |
| Nov 12 CHI @ SF | W 10-6 (4-5) | |
| Nov 22 SF @ GB | L 24-30 (4-6) | |
| Nov 29 JAC @ SF | W 20-3 (5-6) | |
| Dec 06 SF @ SEA | L 17-20 (5-7) | |
| Dec 14 ARI @ SF | W 24-9 (6-7) | |
| Dec 20 SF @ PHI | L 13-27 (6-8) | |
| Dec 27 DET @ SF | W 20-6 (7-8) | |
| Jan 03 SF @ STL | W 28-6 (8-8) | |
| Sept. 7 Arizona Cardinals 4:15 p.m. | L 13-23 (0-1) | |
| Sept. 14 at Seattle Seahawks 4:05 p.m. | W 33-30 (1-1) | |
| Sept. 21 Detroit Lions 4:05 p.m. | W 31-13 (2-1) | |
| Sept. 28 at New Orleans Saints 1 p.m. | L 17-31 (2-2) | |
| Oct. 5 New England Patriots 4:15 p.m. | L 21-30 (2-3) | |
| Oct. 12 Philadelphia Eagles 4:15 p.m. | L 26-40 (2-4) | |
| Oct. 19 at New York Giants 1 p.m. | L 17-29 (2-5) | |
| Oct. 26 Seattle Seahawks 4:15 p.m. | L 13-34 (2-6) | |
| Nov. 2 Bye | Bye | |
| Nov. 10 (Mon.) at Arizona Cardinals 8:30 p.m | L 24-29 (2-6) | |
| Nov. 16 St. Louis Rams 4:05 p.m. | W 35-16 (3-7) | |
| Nov. 23 at Dallas Cowboys 1 p.m. | L 22-35 (3-8) | |
| Nov. 30 at Buffalo Bills 1 p.m. | W 10-3 (4-8) | |
| Dec. 7 New York Jets 4:05 p.m. | W 24-14 (5-8) | |
| Dec. 14 at Miami Dolphins 1 p.m. | L 9-14 (5-9) | |
| Dec. 21 at St. Louis Rams 1 p.m. | W 17-16 (6-9) | |
| Dec. 28 Washington Redskins 4:15 p.m. | W 27-24 (7-9) | |
| Sep 10 Arizona 10:15pm | W 20-17 (1-0) | |
| Sep 16 @St. Louis 1:00pm | W 17-16 (2-0) | |
| Sep 23 @Pittsburgh 1:00pm | L 16-37 (2-1) | |
| Sep 30 Seattle 4:05pm | L 3-23 (2-2) | |
| Oct 7 Baltimore 4:15pm | L 7-9 (2-3) | |
| BYE | BYE | |
| Oct 21 @N.Y. Giants 1:00pm | L 15-33 (2-4) | |
| Oct 28 New Orleans 4:15pm | L 10-31 (2-5) | |
| Nov 4 @Atlanta 1:00pm | L 16-20 (2-6) | |
| Nov 12 @Seattle 8:30pm | L 9-13 (2-7) | |
| Nov 18 St. Louis 4:15pm | W 37-31 (3-7) | |
| Nov 25 @Arizona 4:05pm | L 14-31 (3-8) | |
| Dec 2 @Carolina 1:00pm | L 14-31 (3-9) | |
| Dec 9 Minnesota 4:05pm | L 7-27 (3-10) | |
| Dec 15 Cincinnati 8:15pm | W 20-13 (4-10) | |
| Dec 23 Tampa Bay 8:15pm | W 21-19 (5-10) | |
| Dec 30 @Cleveland 1:00pm | L 7-20 (5-11) | |