| W1 | SEP 7, 2025 |  Green Bay PackersDetroit Lions @ Green Bay Packers | Away | 13 - 27 | Final | Open |
| W2 | SEP 14, 2025 |  Chicago BearsChicago Bears @ Detroit Lions | Home | 21 - 52 | Final | Open |
| W3 | SEP 22, 2025 |  Baltimore RavensDetroit Lions @ Baltimore Ravens | Away | 38 - 30 | Final | Open |
| W4 | SEP 28, 2025 |  Cleveland BrownsCleveland Browns @ Detroit Lions | Home | 10 - 34 | Final | Open |
| W5 | OCT 5, 2025 |  Cincinnati BengalsDetroit Lions @ Cincinnati Bengals | Away | 37 - 24 | Final | Open |
| W6 | OCT 12, 2025 |  Kansas City ChiefsDetroit Lions @ Kansas City Chiefs | Away | 17 - 30 | Final | Open |
| W7 | OCT 20, 2025 |  Tampa Bay BuccaneersTampa Bay Buccaneers @ Detroit Lions | Home | 9 - 24 | Final | Open |
| W8 | - | ByeDetroit Lions Bye Week | - | - | Bye | Rest |
| W9 | NOV 2, 2025 |  Minnesota VikingsMinnesota Vikings @ Detroit Lions | Home | 27 - 24 | Final | Open |
| W10 | NOV 9, 2025 |  Washington CommandersDetroit Lions @ Washington Commanders | Away | 44 - 22 | Final | Open |
| W11 | NOV 16, 2025 |  Philadelphia EaglesDetroit Lions @ Philadelphia Eagles | Away | 9 - 16 | Final | Open |
| W12 | NOV 23, 2025 |  New York GiantsNew York Giants @ Detroit Lions | Home | 27 - 34 | Final | Open |
| W13 | NOV 27, 2025 | Green Bay PackersGreen Bay Packers @ Detroit Lions | Home | 31 - 24 | Final | Open |
| W14 | DEC 4, 2025 |  Dallas CowboysDallas Cowboys @ Detroit Lions | Home | 30 - 44 | Final | Open |
| W15 | DEC 14, 2025 |  Los Angeles RamsDetroit Lions @ Los Angeles Rams | Away | 34 - 41 | Final | Open |
| W16 | DEC 21, 2025 |  Pittsburgh SteelersPittsburgh Steelers @ Detroit Lions | Home | 29 - 24 | Final | Open |
| W17 | DEC 25, 2025 | Minnesota VikingsDetroit Lions @ Minnesota Vikings | Away | 10 - 23 | Final | Open |
| W18 | JAN 4, 2026 | Chicago BearsDetroit Lions @ Chicago Bears | Away | 19 - 16 | Final | Open |
