After a goalless first half, the visitor was more clinical in a decisive second period.
Omri Gandelman put Lecce ahead with a header after 65 minutes, and Ylber Ramadani doubled the lead 11 minutes later with a powerful shot into the bottom corner.
It was the second win in a row for Lecce after a run of eight games without a victory and only the second time in 12 games it has scored twice in one match.
It was the second loss in succession for Cagliari, which remained in 13th place, a point behind Parma and one clear of Torino.
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AP soccer: https://apnews.com/hub/soccer
