The Cardinals, were led by 14th-year head coach Jeff Walz, and played their home games at the KFC Yum!

On January 18, 2021, following a 12–0 start, the Cardinals were ranked number 1 in the AP Poll for the first time in program history, garnering 20 of 29 first place votes.

In the ACC tournament, they defeated Wake Forest in the Quarterfinals and Syracuse before losing in the Final NC State.

They defeated Syracuse in the Quarterfinals before losing to eventual champions NC State in the Semifinals.

A This is the first time Louisville has been ranked number 1 in the AP Women's Basketball Poll in program history.