Numerous Best Games this weekend, 5 upsets, and 4 Best Upsets (marked with an asterisks below).
| – | Team | Rank | VS | Rank | Opp Team | Details |
| 1 | North Carolina | #1 | 11 – 10 | #4 | Notre Dame | 04/10/2021 |
| 2 | Syracuse | #2 | 15 – 12 | #6 | Virginia | 04/10/2021 |
| 3* | Penn State | #16 | 16 – 9 | #12 | Maryland | 04/11/2021 |
| 4 | Johns Hopkins | #14 | 17 – 10 | #24 | Rutgers | 04/11/2021 |
| 5 | Denver | #15 | 11 – 7 | #31 | UConn | 04/11/2021 |
| 6 | Denver | #15 | 14 – 13 | #31 | UConn | 04/09/2021 |
| 7 | Temple | #21 | 10 – 8 | #32 | Cincinnati | 04/11/2021 |
| 8 | Temple | #21 | 16 – 14 | #32 | Cincinnati | 04/09/2021 |
| 9 | Boston College | #3 | 21 – 11 | #54 | Virginia Tech | 04/10/2021 |
| 10 | Hofstra | #25 | 13 – 7 | #33 | James Madison | 04/10/2021 |
| 11 | UMass | #26 | 21 – 12 | #41 | Saint Joseph’s | 04/09/2021 |
| 12 | Lehigh | #35 | 12 – 7 | #40 | Navy | 04/10/2021 |
| 13 | UC Davis | #36 | 19 – 10 | #51 | San Diego State | 04/11/2021 |
| 14 | Towson | #18 | 20 – 10 | #69 | William and Mary | 04/10/2021 |
| 15 | Georgetown | #42 | 20 – 10 | #48 | Marquette | 04/11/2021 |
| 16* | Marquette | #48 | 15 – 9 | #42 | Georgetown | 04/09/2021 |
| 17 | Elon | #20 | 19 – 3 | #73 | VCU | 04/11/2021 |
| 18 | UAlbany | #29 | 19 – 7 | #64 | UMBC | 04/09/2021 |
| 19* | San Diego State | #51 | 14 – 13 | #44 | USC | 04/09/2021 |
| 20 | Colorado | #27 | 12 – 10 | #70 | California | 04/11/2021 |
| 21 | Davidson | #28 | 15 – 9 | #73 | VCU | 04/09/2021 |
| 22* | Siena | #67 | 15 – 11 | #45 | Fairfield | 04/10/2021 |
| 23 | Liberty | #46 | 14 – 13 | #68 | Coastal Carolina | 04/10/2021 |
| 24 | Saint Joseph’s | #41 | 19 – 9 | #77 | La Salle | 04/11/2021 |
| 25 | Bucknell | #57 | 13 – 11 | #66 | Colgate | 04/10/2021 |
