Numerous Best Games this weekend and 1 Best Upsets (marked with an asterisks below).
| – | Team | Rank | VS | Rank | Opp Team | Details |
| 1 | Cumberlands (Ky.) | #1 | 11 – 9 | #4 | Life (Ga.) | 04/09/2021 |
| 2 | Concordia (Mich.) | #5 | 20 – 9 | #10 | Indiana Tech | 04/10/2021 |
| 3 | Benedictine (Kan.) | #13 | 19 – 2 | #14 | Missouri Baptist | 04/10/2021 |
| 4 | Reinhardt (Ga.) | #3 | 26 – 5 | #24 | Point (Ga.) | 04/10/2021 |
| 5 | Keiser (Fla.) | #2 | 19 – 8 | #30 | Ave Maria (Fla.) | 04/10/2021 |
| 6 | Georgetown (Ky.) | #12 | 15 – 8 | #25 | Marian (Ind.) | 04/11/2021 |
| 7 | St. Ambrose (Iowa) | #7 | 10 – 9 | #34 | Missouri Valley | 04/10/2021 |
| 8 | St. Andrews (N.C.) | #11 | 19 – 2 | #32 | Brenau (Ga.) | 04/09/2021 |
| 9 | Aquinas (Mich.) | #9 | 27 – 1 | #43 | Lourdes (Ohio) | 04/10/2021 |
| 10 | St. Ambrose (Iowa) | #7 | 19 – 4 | #48 | Saint Mary (Kan.) | 04/11/2021 |
| 11* | Midland (Neb.) | #41 | 11 – 10 | #28 | William Penn (Iowa) | 04/10/2021 |
| 12 | William Penn (Iowa) | #28 | 21 – 2 | #49 | Morningside (Iowa) | 04/09/2021 |
| 13 | Missouri Valley | #34 | 12 – 10 | #47 | Clarke (Iowa) | 04/09/2021 |
| 14 | Midland (Neb.) | #41 | 14 – 10 | #45 | Culver-Stockton (Mo.) | 04/09/2021 |
| 15 | Culver-Stockton (Mo.) | #45 | 21 – 6 | #49 | Morningside (Iowa) | 04/11/2021 |
| 16 | Clarke (Iowa) | #47 | 18 – 9 | #48 | Saint Mary (Kan.) | 04/10/2021 |
