[1] Defending champions Northwest Missouri State defeated West Texas A&M in the championship game, 80–54, to claim the Bearcats' second consecutive and third overall Division II national title.

Biola, Flagler, Fresno Pacific, Lee, Malone, Northwest Nazarene, Nyack, Oklahoma Baptist, and Southern Arkansas qualified for the Division II tournament for the first time.

The field size was temporarily reduced for just the 2021 championship to account for teams and conferences that chose to not compete during the 2020–21 season due to the COVID-19 pandemic.

Teams from four conferences (CCAA, CIAA, Northeast-10, and Sunshine State) did not participate in the regular season or the tournament.

[2] Each region consisted of two automatic qualifiers (the teams who won their respective conference tournaments) and at-large bids.