| 9/2/2021 | South Florida | 0 | at | North Carolina State | 45 | AAC | ||
| 9/3/2021 | Duke | 28 | at | UNC-Charlotte | 31 | @ CUSA | ||
| North Carolina | 10 | at | Virginia Tech | 17 | ||||
| Old Dominion | 10 | at | Wake Forest | 42 | CUSA | |||
| 9/4/2021 | Colgate | 0 | at | Boston College | 51 | Pat (1AA) | ||
| Georgia | 10 | vs | Clemson | 3 | Charlotte NC | vs SEC | ||
| Northern Illinois | 22 | at | Georgia Tech | 21 | MAC | |||
| Alabama | 44 | vs | Miami-Florida | 13 | Atlanta GA | vs SEC | ||
| Syracuse | 29 | at | Ohio | 9 | @ MAC | |||
| Massachusetts | 7 | at | Pittsburgh | 51 | Ind | |||
| William & Mary | 0 | at | Virginia | 43 | CAAF (1AA) | |||
| 9/5/2021 | Notre Dame | 41 | at | Florida State | 38 | OT | ND | |
| 9/6/2021 | Louisville | 24 | vs | Mississippi | 43 | Atlanta GA | vs SEC | |
| 9/10/2021 | North Carolina A&T | 17 | at | Duke | 45 | BigS (1AA) | ||
| 9/11/2021 | South Carolina State | 3 | at | Clemson | 49 | MEAC (1AA) | ||
| Jacksonville State | 20 | at | Florida State | 17 | WAC (1AA) | |||
| Kennesaw St | 17 | at | Georgia Tech | 45 | BigS (1AA) | |||
| Eastern Kentucky | 3 | at | Louisville | 30 | WAC (1AA) | |||
| Boston College | 45 | at | Massachusetts | 28 | @ Ind | |||
| Appalachian State | 23 | at | Miami-Florida | 25 | SBC | |||
| North Carolina State | 10 | at | Mississippi State | 24 | @ SEC | |||
| Georgia State | 17 | at | North Carolina | 59 | SBC | |||
| Rutgers | 17 | at | Syracuse | 7 | B10 | |||
| Pittsburgh | 41 | at | Tennessee | 34 | @ SEC | |||
| Illinois | 14 | at | Virginia | 42 | B10 | |||
| Middle Tenn State | 14 | at | Virginia Tech | 35 | CUSA | |||
| Norfolk State | 16 | at | Wake Forest | 41 | MEAC (1AA) | |||
| 9/17/2021 | UCF | 35 | at | Louisville | 42 | AAC | ||
| 9/18/2021 | Georgia Tech | 8 | at | Clemson | 14 | |||
| Northwestern | 23 | at | Duke | 30 | B10 | |||
| Michigan State | 38 | at | Miami-Florida | 17 | B10 | |||
| Virginia | 39 | at | North Carolina | 59 | ||||
| Furman | 7 | at | North Carolina State | 45 | SoCon (1AA) | |||
| Western Michigan | 44 | at | Pittsburgh | 41 | MAC | |||
| Albany NY | 24 | at | Syracuse | 62 | CAAF (1AA) | |||
| Boston College | 28 | at | Temple | 3 | @ AAC | |||
| Florida State | 14 | at | Wake Forest | 35 | ||||
| Virginia Tech | 21 | at | West Virginia | 27 | @ B12 | |||
| 9/24/2021 | Liberty | 21 | at | Syracuse | 24 | Ind | ||
| Wake Forest | 37 | at | Virginia | 17 | ||||
| 9/25/2021 | Missouri | 34 | at | Boston College | 41 | OT | SEC | |
| Kansas | 33 | at | Duke | 52 | B12 | |||
| Louisville | 31 | at | Florida State | 23 | ||||
| North Carolina | 22 | at | Georgia Tech | 45 | ||||
| Central Conn | 0 | at | Miami-Florida | 69 | NE (1AA) | |||
| Clemson | 21 | at | North Carolina State | 27 | 2OT | |||
| New Hampshire | 7 | at | Pittsburgh | 77 | CAAF (1AA) | |||
| Richmond | 10 | at | Virginia Tech | 21 | CAAF (1AA) | |||
| 9/30/2021 | Virginia | 30 | at | Miami-Florida | 28 | |||
| 10/2/2021 | Boston College | 13 | at | Clemson | 19 | |||
| Syracuse | 30 | at | Florida State | 33 | ||||
| Pittsburgh | 52 | at | Georgia Tech | 21 | ||||
| Duke | 7 | at | North Carolina | 38 | ||||
| Louisiana Tech | 27 | at | North Carolina State | 34 | CUSA | |||
| Louisville | 34 | at | Wake Forest | 37 | ||||
| 10/9/2021 | Georgia Tech | 31 | at | Duke | 27 | |||
| Virginia | 34 | at | Louisville | 33 | ||||
| Florida State | 35 | at | North Carolina | 25 | ||||
| Wake Forest | 40 | at | Syracuse | 37 | OT | |||
| Notre Dame | 32 | at | Virginia Tech | 29 | ND | |||
| 10/15/2021 | Clemson | 17 | at | Syracuse | 14 | |||
| 10/16/2021 | North Carolina State | 33 | at | Boston College | 7 | |||
| Miami-Florida | 42 | at | North Carolina | 45 | ||||
| Duke | 0 | at | Virginia | 48 | ||||
| Pittsburgh | 28 | at | Virginia Tech | 7 | ||||
| 10/23/2021 | Wake Forest | 70 | at | Army | 56 | @ Ind | ||
| Massachusetts | 3 | at | Florida State | 59 | Ind | |||
| Boston College | 14 | at | Louisville | 28 | ||||
| North Carolina State | 30 | at | Miami-Florida | 31 | ||||
| Clemson | 17 | at | Pittsburgh | 27 | ||||
| Georgia Tech | 40 | at | Virginia | 48 | ||||
| Syracuse | 41 | at | Virginia Tech | 36 | ||||
| 10/30/2021 | Virginia | 49 | at | BYU | 66 | @ Ind | ||
| Florida State | 20 | at | Clemson | 30 | ||||
| Virginia Tech | 26 | at | Georgia Tech | 17 | ||||
| Louisville | 13 | at | North Carolina State | 28 | ||||
| North Carolina | 34 | at | Notre Dame | 44 | @ ND | |||
| Miami-Florida | 38 | at | Pittsburgh | 34 | ||||
| Boston College | 6 | at | Syracuse | 21 | ||||
| Duke | 7 | at | Wake Forest | 45 | ||||
| 11/5/2021 | Virginia Tech | 3 | at | Boston College | 17 | |||
| 11/6/2021 | Pittsburgh | 54 | at | Duke | 29 | |||
| North Carolina State | 28 | at | Florida State | 14 | ||||
| Clemson | 30 | at | Louisville | 24 | ||||
| Georgia Tech | 30 | at | Miami-Florida | 33 | ||||
| Wake Forest | 55 | at | North Carolina | 58 | ||||
| 11/11/2021 | North Carolina | 23 | at | Pittsburgh | 30 | OT | ||
| 11/13/2021 | Connecticut | 7 | at | Clemson | 44 | Ind | ||
| Miami-Florida | 28 | at | Florida State | 31 | ||||
| Boston College | 41 | at | Georgia Tech | 30 | ||||
| Syracuse | 3 | at | Louisville | 41 | ||||
| Notre Dame | 28 | at | Virginia | 3 | ND | |||
| Duke | 17 | at | Virginia Tech | 48 | ||||
| North Carolina State | 42 | at | Wake Forest | 45 | ||||
| 11/18/2021 | Louisville | 62 | at | Duke | 22 | |||
| 11/20/2021 | Florida State | 26 | at | Boston College | 23 | |||
| Wake Forest | 27 | at | Clemson | 48 | ||||
| Virginia Tech | 26 | at | Miami-Florida | 38 | ||||
| Wofford | 14 | at | North Carolina | 34 | SoCon (1AA) | |||
| Syracuse | 17 | at | North Carolina State | 41 | ||||
| Georgia Tech | 0 | at | Notre Dame | 55 | @ ND | |||
| Virginia | 38 | at | Pittsburgh | 48 | ||||
| 11/26/2021 | North Carolina | 30 | at | North Carolina State | 34 | |||
| 11/27/2021 | Wake Forest | 41 | at | Boston College | 10 | |||
| Miami-Florida | 47 | at | Duke | 10 | ||||
| Florida State | 21 | at | Florida | 24 | @ SEC | |||
| Georgia | 45 | at | Georgia Tech | 0 | SEC | |||
| Kentucky | 52 | at | Louisville | 21 | SEC | |||
| Clemson | 30 | at | South Carolina | 0 | @ SEC | |||
| Pittsburgh | 31 | at | Syracuse | 14 | ||||
| Virginia Tech | 29 | at | Virginia | 24 | ||||
| 12/4/2021 | Pittsburgh | 45 | vs | Wake Forest | 21 | ACC Championship - Charlotte NC | ||
| 12/27/2021 | Boston College | vs | East Carolina | Cancelled Military Bowl - Annapolis MD | vs AAC | |||
| 12/28/2021 | Air Force | 31 | vs | Louisville | 28 | First Responder Bowl - Dallas TX | vs MW | |
| UCLA | vs | North Carolina State | Cancelled Holiday Bowl - San Diego CA | vs P12 | ||||
| 12/29/2021 | Clemson | 20 | vs | Iowa State | 13 | Cheez-It Bowl - Orlando FL | vs B12 | |
| SMU | vs | Virginia | Cancelled Wasabi Fenway Bowl - Boston MA | vs AAC | ||||
| Maryland | 54 | vs | Virginia Tech | 10 | Pinstribe Bowl - Bronx NY | vs B10 | ||
| 12/30/2021 | Pittsburgh | 21 | vs | Michigan State | 31 | Peach Bowl - Atlanta GA | vs B10 | |
| North Carolina | 21 | vs | South Carolina | 38 | Dukes Mayo Bowl - Charlotte NC | vs SEC | ||
| 12/31/2021 | Wake Forest | 38 | vs | Rutgers | 10 | Gator Bowl - Jacksonville FL | vs B10 |