13 games
| Date | Site | Opp AP | Opponent | UL AP | W/L | UL | Opp | OT | Overall | Conf | Attendance | City | State | Stadium | Event |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 09/01/2016 | H | Charlotte | 19 | W | 70 | 14 | 1-0 | 53,127 | Louisville | Ky. | Papa John's Cardinal Stadium | ||||
| 09/09/2016 | A | Syracuse | 13 | W | 62 | 28 | 2-0 | 1-0 | 32,184 | Syracuse | N.Y. | Carrier Dome | |||
| 09/17/2016 | H | 2 | Florida State | 10 | W | 63 | 20 | 3-0 | 2-0 | 55,632 | Louisville | Ky. | Papa John's Cardinal Stadium | ||
| 09/24/2016 | A | Marshall | 3 | W | 59 | 28 | 4-0 | 2-0 | 40,592 | Huntington | W.Va. | Joan C. Edwards Stadium | |||
| 10/01/2016 | A | 5 | Clemson | 3 | L | 36 | 42 | 4-1 | 2-1 | 83,362 | Clemson | S.C. | Memorial Stadium | ||
| 10/14/2016 | H | Duke | 7 | W | 24 | 14 | 5-1 | 3-1 | 55,121 | Louisville | Ky. | Papa John's Cardinal Stadium | |||
| 10/22/2016 | H | North Carolina State | 7 | W | 54 | 13 | 6-1 | 4-1 | 55,218 | Louisville | Ky. | Papa John's Cardinal Stadium | |||
| 10/29/2016 | A | Virginia | 5 | W | 32 | 25 | 7-1 | 5-1 | 34,824 | Charlottesville | Va. | Scott Stadium | |||
| 11/05/2016 | A | Boston College | 5 | W | 52 | 7 | 8-1 | 6-1 | 30,644 | Chestnut Hill | Mass. | Alumni Stadium | |||
| 11/12/2016 | H | Wake Forest | 5 | W | 44 | 12 | 9-1 | 7-1 | 51,218 | Louisville | Ky. | Papa John's Cardinal Stadium | |||
| 11/17/2016 | A | Houston | 3 | L | 10 | 36 | 9-2 | 7-1 | 42,822 | Houston | Texas | TDECU Stadium | |||
| 11/26/2016 | H | Kentucky | 11 | L | 38 | 41 | 9-3 | 7-1 | 54,075 | Louisville | Ky. | Papa John's Cardinal Stadium | |||
| 12/31/2016 | N | 19 | Louisiana State | 15 | L | 9 | 29 | 9-4 | 7-1 | 46,063 | Orlando | Fla. | Camping World Stadium | Citrus Bowl |