U.S. Città di Palermo played the season 2005-06 in the Serie A league, the second consecutive time since the 2004 promotion. During this season, Palermo also competed in the UEFA Cup, thus making its historical first appearance in a European competition.

After having ended the 2004-05 Serie A campaign in sixth place, Palermo automatically qualified to the next UEFA Cup for an historical first time. Meanwhile, Francesco Guidolin resigned following the last matchday and Luigi Delneri was appointed to replace him. The summer market was heavily conditioned by the sale of powerful striker Luca Toni to Fiorentina for €10mln in a highly controversial move. Two young strikers, Andrea Caracciolo from Brescia and Stephen Makinwa from Atalanta, were signed as potential replacements for Toni.

Palermo had a good start in the season, showing a spectacular style of playing with impressive results, with an exciting 3-2 home win against Inter Milan as the highest point of the first half of the season. Palermo also successfully passed to the UEFA Cup group stage, after having defeated Cypriot side Anorthosis Famagusta FC in a 6-1 aggregate win. The club also succeeded to win its UEFA Cup round against the likes of RCD Espanyol, FC Lokomotiv Moscow, Maccabi Petah Tikva F.C. and Brøndby IF.

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