| W1 | SEP 7, 2025 |  Seattle SeahawksSan Francisco 49ers @ Seattle Seahawks | Away | 17 - 13 | Final | Open |
| W2 | SEP 14, 2025 |  New Orleans SaintsSan Francisco 49ers @ New Orleans Saints | Away | 26 - 21 | Final | Open |
| W3 | SEP 21, 2025 |  Arizona CardinalsArizona Cardinals @ San Francisco 49ers | Home | 15 - 16 | Final | Open |
| W4 | SEP 28, 2025 |  Jacksonville JaguarsJacksonville Jaguars @ San Francisco 49ers | Home | 26 - 21 | Final | Open |
| W5 | OCT 2, 2025 |  Los Angeles RamsSan Francisco 49ers @ Los Angeles Rams | Away | 26 - 23 | Final | Open |
| W6 | OCT 12, 2025 |  Tampa Bay BuccaneersSan Francisco 49ers @ Tampa Bay Buccaneers | Away | 19 - 30 | Final | Open |
| W7 | OCT 19, 2025 |  Atlanta FalconsAtlanta Falcons @ San Francisco 49ers | Home | 10 - 20 | Final | Open |
| W8 | OCT 26, 2025 |  Houston TexansSan Francisco 49ers @ Houston Texans | Away | 15 - 26 | Final | Open |
| W9 | NOV 2, 2025 |  New York GiantsSan Francisco 49ers @ New York Giants | Away | 34 - 24 | Final | Open |
| W10 | NOV 9, 2025 | Los Angeles RamsLos Angeles Rams @ San Francisco 49ers | Home | 42 - 26 | Final | Open |
| W11 | NOV 16, 2025 | Arizona CardinalsSan Francisco 49ers @ Arizona Cardinals | Away | 41 - 22 | Final | Open |
| W12 | NOV 24, 2025 |  Carolina PanthersCarolina Panthers @ San Francisco 49ers | Home | 9 - 20 | Final | Open |
| W13 | NOV 30, 2025 |  Cleveland BrownsSan Francisco 49ers @ Cleveland Browns | Away | 26 - 8 | Final | Open |
| W14 | - | ByeSan Francisco 49ers Bye Week | - | - | Bye | Rest |
| W15 | DEC 14, 2025 |  Tennessee TitansTennessee Titans @ San Francisco 49ers | Home | 24 - 37 | Final | Open |
| W16 | DEC 22, 2025 |  Indianapolis ColtsSan Francisco 49ers @ Indianapolis Colts | Away | 48 - 27 | Final | Open |
| W17 | DEC 28, 2025 |  Chicago BearsChicago Bears @ San Francisco 49ers | Home | 38 - 42 | Final | Open |
| W18 | JAN 3, 2026 | Seattle SeahawksSeattle Seahawks @ San Francisco 49ers | Home | 13 - 3 | Final | Open |
