| Date | Opponent | Time/TV | Tickets | |
| Sunday Sep 5, 2021 |  | at Florida State Seminoles Doak Campbell Stadium, Tallahassee, FL | 7:30 PM ET ABC | Won 41-38 (OT) |
| Saturday Sep 11, 2021 |  | Toledo Rockets Notre Dame Stadium, South Bend, IN | 2:30 PM ET Peacock | Won 32-29 |
| Saturday Sep 18, 2021 |  | Purdue Boilermakers Notre Dame Stadium, South Bend, IN | 2:30 PM ET NBC | Won 27-13 |
| Saturday Sep 25, 2021 |  | Wisconsin Badgers Soldier Field, Chicago, IL | 12:00 PM ET FOX | Won 41-13 |
| Saturday Oct 2, 2021 |  | Cincinnati Bearcats Notre Dame Stadium, South Bend, IN | 2:30 PM ET NBC | Lost 24-13 |
| Saturday Oct 9, 2021 |  | at Virginia Tech Hokies Lane Stadium, Blacksburg, VA | 7:30 PM ET ACCN | Won 32-29 |
| Saturday Oct 16, 2021 | Bye Week | |||
| Saturday Oct 23, 2021 |  | USC Trojans Notre Dame Stadium, South Bend, IN | 7:30 PM ET NBC | Won 31-16 |
| Saturday Oct 30, 2021 |  | North Carolina Tar Heels Notre Dame Stadium, South Bend, IN | 7:30 PM ET NBC | Won 44-34 |
| Saturday Nov 6, 2021 |  | Navy Midshipmen Notre Dame Stadium, South Bend, IN | 3:30 PM ET NBC | Won 34-6 |
| Saturday Nov 13, 2021 |  | at Virginia Cavaliers Scott Stadium, Charlottesville, VA | 7:30 PM ET ABC | Won 28-3 |
| Saturday Nov 20, 2021 |  | Georgia Tech Yellow Jackets Notre Dame Stadium, South Bend, IN | 2:30 PM ET NBC | Won 55-0 |
| Saturday Nov 27, 2021 |  | at Stanford Cardinal Stanford Stadium, Stanford, CA | 8:00 PM ET FOX | Won 45-14 |
| Saturday Jan 1, 2022 |  | Oklahoma State Cowboys Fiesta Bowl State Farm Stadium, Glendale, AZ | 1:00 PM ET ESPN | Lost 37-35 |
