Numerous Best Games this weekend (below), 0 Upsets, and 0 Best Upsets.
| – | Team | Rank | VS | Rank | Opp Team | Details |
| 1 | SCAD Savannah (Ga.) | #8 | 18 – 12 | #12 | St. Andrews (N.C.) | 04/16/2021 |
| 2 | Cumberlands (Ky.) | #1 | 19 – 5 | #28 | Marian (Ind.) | 04/16/2021 |
| 3 | Lawrence Tech (Mich.) | #16 | 17 – 7 | #21 | Bethel (Ind.) | 04/16/2021 |
| 4 | Georgetown (Ky.) | #14 | 21 – 2 | #25 | Thomas More (Ky.) | 04/17/2021 |
| 5 | Missouri Baptist | #10 | 15 – 11 | #39 | Missouri Valley | 04/17/2021 |
| 6 | Ottawa (Kan.) | #19 | 15 – 3 | #30 | William Penn (Iowa) | 04/17/2021 |
| 7 | St. Ambrose (Iowa) | #7 | 23 – 5 | #43 | Midland (Neb.) | 04/17/2021 |
| 8 | Benedictine (Kan.) | #11 | 27 – 1 | #47 | Culver-Stockton (Mo.) | 04/17/2021 |
| 9 | Madonna (Mich.) | #18 | 25 – 2 | #46 | Lourdes (Ohio) | 04/17/2021 |
