Vllaznia defended the trophy, winning their eighth title in the competition.
Ties were played in a two-legged format similar to those of European competitions.
If the aggregate score was tied after both games, the match was decided by extra time and a penalty shoot-out, if necessary.
[1] In order to reduce the number of participating teams for the First round to 32, a preliminary tournament is played.
The matches were played on 22 September 2021, 13 and 14 October 2021.
Dinamo Tirana advanced to the quarter finals.
Skënderbeu advanced to the quarter finals.
Egnatia advanced to the quarter finals.
All eight qualified teams from the second round progressed to the quarter-finals.