Numerous Best Games this weekend (below), 4 Upsets, and 0 Best Upsets (which are marked with an asterisks).
| – | Team | Rank | VS | Rank | Opp Team | Details |
| 1 | RIT | #1 | 15 – 5 | #17 | St. Lawrence | 04/17/2021 |
| 2 | York | #7 | 20 – 5 | #35 | Misericordia | 04/16/2021 |
| 3 | Stevenson | #9 | 16 – 9 | #51 | Widener | 04/17/2021 |
| 4 | Franklin and Marshall | #11 | 12 – 5 | #58 | Washington | 04/17/2021 |
| 5 | Cortland | #18 | 14 – 13 | #57 | Geneseo | 04/16/2021 |
| 6 | Southern Virginia | #12 | 18 – 15 | #65 | Mary Washington | 04/17/2021 |
| 7 | Lynchburg | #3 | 20 – 8 | #75 | Bridgewater | 04/17/2021 |
| 8 | Cortland | #18 | 21 – 5 | #63 | Oneonta | 04/18/2021 |
| 9 | Tufts | #8 | 27 – 11 | #79 | Wesleyan | 04/18/2021 |
| 10 | Tufts | #8 | 24 – 16 | #88 | Connecticut College | 04/17/2021 |
| 11 | Washington and Lee | #10 | 17 – 1 | #98 | Shenandoah | 04/18/2021 |
| 12 | Cabrini | #19 | 23 – 3 | #100 | Neumann | 04/17/2021 |
| 13 | Albion | #59 | 15 – 14 | #62 | Hope | 04/17/2021 |
| 14 | Elizabethtown | #52 | 12 – 3 | #71 | Moravian | 04/17/2021 |
| 15 | Endicott | #28 | 22 – 2 | #105 | Wentworth | 04/17/2021 |
| 16 | Ursinus | #34 | 14 – 9 | #99 | Dickinson | 04/17/2021 |
| 17 | SUNY Maritime | #49 | 14 – 12 | #86 | Farmingdale | 04/17/2021 |
| 18 | Scranton | #23 | 11 – 6 | #126 | Susquehanna | 04/17/2021 |
| 19 | Lebanon Valley | #45 | 11 – 9 | #106 | Messiah | 04/17/2021 |
| 20 | Western New England | #42 | 21 – 5 | #116 | Curry | 04/17/2021 |
| 21 | Williams | #38 | 18 – 5 | #120 | Hamilton | 04/17/2021 |
| 22 | John Carroll | #15 | 25 – 4 | #147 | Marietta | 04/17/2021 |
| 23 | Colby | #72 | 17 – 10 | #93 | Bates | 04/18/2021 |
| 24 | Kenyon | #31 | 15 – 7 | #134 | Wooster | 04/17/2021 |
| 25 | Union | #39 | 19 – 5 | #132 | Vassar | 04/17/2021 |
