City reached the Eastern Conference Final, or semifinals of the USL Championship Playoffs before losing to the Tampa Bay Rowdies.

Lancaster, along with league Goalkeeper of the Year Ben Lundt, defender Sean Totsch, and midfielder Speedy Williams, were named to the All-League First Team.

Louisville City faced San Diego Loyal SC, Colorado Springs Switchbacks FC, and New Mexico United for the first time in their history.

[5] For the first time in their history, Louisville City completed a full-length regular season without a player being sent off, and without a multi-goal loss, accomplishments the team would sustain through the playoff run.

[7] On July 20, 2021, in conjunction with announcing a tentative schedule for the 2022 U.S. Open Cup, the U.S. Soccer Federation also declared that the 2021 edition of the competition was officially cancelled.