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The 1980–81 Cypriot Cup was the 39th edition of the Cypriot Cup. A total of 41 clubs entered the competition. It began on 20 December 1980 with the preliminary round and concluded on 27 June 1981 with the replay final which was held at Tsirion Stadium. Omonia won their 5th Cypriot Cup trophy after beating Enosis Neon Paralimni 3–0 in the final.
The competition consisted of six knock-out rounds. In all rounds each tie was played as a single leg and was held at the home ground of one of the two teams, according to the draw results. Each tie winner was qualifying to the next round. If a match was drawn, extra time was following. If extra time was drawn, there was a replay at the ground of the team who were away for the first game. If the rematch was also drawn, then extra time was following and if the match remained drawn after extra time the winner was decided by penalty shoot-out.
In the first preliminary draw, participated all the 13 teams of the Cypriot Third Division and 5 of the 14 teams of the Cypriot Second Division (last five of the league table of each group at the day of the draw).