| W1 | SEP 7, 2025 |  Miami DolphinsMiami Dolphins @ Indianapolis Colts | Home | 8 - 33 | Final | Open |
| W2 | SEP 14, 2025 |  Denver BroncosDenver Broncos @ Indianapolis Colts | Home | 28 - 29 | Final | Open |
| W3 | SEP 21, 2025 |  Tennessee TitansIndianapolis Colts @ Tennessee Titans | Away | 41 - 20 | Final | Open |
| W4 | SEP 28, 2025 |  Los Angeles RamsIndianapolis Colts @ Los Angeles Rams | Away | 20 - 27 | Final | Open |
| W5 | OCT 5, 2025 |  Las Vegas RaidersLas Vegas Raiders @ Indianapolis Colts | Home | 6 - 40 | Final | Open |
| W6 | OCT 12, 2025 |  Arizona CardinalsArizona Cardinals @ Indianapolis Colts | Home | 27 - 31 | Final | Open |
| W7 | OCT 19, 2025 |  Los Angeles ChargersIndianapolis Colts @ Los Angeles Chargers | Away | 38 - 24 | Final | Open |
| W8 | OCT 26, 2025 | Tennessee TitansTennessee Titans @ Indianapolis Colts | Home | 14 - 38 | Final | Open |
| W9 | NOV 2, 2025 |  Pittsburgh SteelersIndianapolis Colts @ Pittsburgh Steelers | Away | 20 - 27 | Final | Open |
| W10 | NOV 9, 2025 |  Atlanta FalconsAtlanta Falcons @ Indianapolis Colts | Home | 25 - 31 | Final | Open |
| W11 | - | ByeIndianapolis Colts Bye Week | - | - | Bye | Rest |
| W12 | NOV 23, 2025 |  Kansas City ChiefsIndianapolis Colts @ Kansas City Chiefs | Away | 20 - 23 | Final | Open |
| W13 | NOV 30, 2025 |  Houston TexansHouston Texans @ Indianapolis Colts | Home | 20 - 16 | Final | Open |
| W14 | DEC 7, 2025 |  Jacksonville JaguarsIndianapolis Colts @ Jacksonville Jaguars | Away | 19 - 36 | Final | Open |
| W15 | DEC 14, 2025 |  Seattle SeahawksIndianapolis Colts @ Seattle Seahawks | Away | 16 - 18 | Final | Open |
| W16 | DEC 22, 2025 |  San Francisco 49ersSan Francisco 49ers @ Indianapolis Colts | Home | 48 - 27 | Final | Open |
| W17 | DEC 28, 2025 | Jacksonville JaguarsJacksonville Jaguars @ Indianapolis Colts | Home | 23 - 17 | Final | Open |
| W18 | JAN 4, 2026 | Houston TexansIndianapolis Colts @ Houston Texans | Away | 30 - 38 | Final | Open |
