Numerous Best Games this weekend, 7 upsets, and 3 Best Upsets (marked with an asterisks below).
| – | Team | Rank | VS | Rank | Opp Team | Details |
| 1* | Rollins | #5 | 14 – 13 | #4 | Florida Southern | 04/09/2021 |
| 2 | Le Moyne | #1 | 14 – 4 | #34 | New Haven | 04/10/2021 |
| 3 | Grand Valley State | #10 | 15 – 13 | #26 | Davenport | 04/10/2021 |
| 4* | Bentley | #24 | 10 – 7 | #15 | Assumption | 04/10/2021 |
| 5 | West Chester | #8 | 16 – 8 | #36 | Shippensburg | 04/10/2021 |
| 6 | Bloomsburg | #17 | 15 – 11 | #28 | Shepherd | 04/10/2021 |
| 7 | Tampa | #3 | 17 – 6 | #50 | Lynn | 04/10/2021 |
| 8 | Queens | #7 | 23 – 5 | #48 | UVa-Wise | 04/10/2021 |
| 9 | Seton Hill | #9 | 18 – 9 | #47 | Indiana (PA) | 04/10/2021 |
| 10 | Saint Leo | #13 | 17 – 14 | #45 | Palm Beach Atl. | 04/10/2021 |
| 11 | Mercyhurst | #23 | 13 – 11 | #37 | Slippery Rock | 04/10/2021 |
| 12 | Frostburg State | #33 | 20 – 9 | #35 | Notre Dame (OH) | 04/11/2021 |
| 13 | Jefferson | #14 | 14 – 13 | #57 | Molloy | 04/10/2021 |
| 14 | UIndy | #2 | 22 – 2 | #79 | Rockhurst | 04/11/2021 |
| 15 | Lee | #31 | 13 – 12 | #52 | Alabama-Huntsville | 04/11/2021 |
| 16 | UIndy | #2 | 26 – 5 | #82 | Missouri Western | 04/09/2021 |
| 17 | Assumption | #15 | 10 – 9 | #70 | Stonehill | 04/10/2021 |
| 18 | Lindenwood | #6 | 22 – 4 | #89 | Quincy | 04/09/2021 |
| 19 | Lindenwood | #6 | 18 – 3 | #96 | Maryville | 04/11/2021 |
| 20* | Findlay | #60 | 15 – 10 | #42 | Walsh University | 04/11/2021 |
| 21 | Limestone | #16 | 21 – 3 | #86 | Coker | 04/10/2021 |
| 22 | Mount Olive | #18 | 15 – 1 | #84 | Southern Wesleyan | 04/09/2021 |
| 23 | St. Thomas Aquinas | #29 | 16 – 4 | #80 | Bridgeport | 04/10/2021 |
| 24 | Barton | #40 | 17 – 5 | #77 | North Greenville | 04/10/2021 |
| 25 | Montevallo | #44 | 18 – 17 | #74 | Young Harris | 04/11/2021 |
