Youth team coach Diego Bortoluzzi was immediately named as a replacement for the Uruguayan who presided over seven defeats, two draws and one win in his 10 games in charge.
After losing their last five games, culminating in Sunday's 4-0 defeat at AC Milan, Palermo are one place off the bottom in Serie A and eight adrift of safety with seven matches to play.
"I have inherited a team which is going through a difficult time and I am trying everything possible to get the team to react with their heads up," said club president Paul Baccaglini in a statement.
"I have offered the team a reward for staying up. This should be a strong sign from the club to the players to show how much we believe in and will fight for this aim."
"A big shake-up is needed," he added. "To that end we have decided to relieve Diego Lopez of his duties as coach, he inherited a difficult situation and we thank him for his hard work."
Baccaglini, a U.S-born businessman, was named as president last month after he agreed that his fund would take over the club.
He replaced the flamboyant Maurizio Zamparini who oversaw nearly 40 coaching changes during his 15 turbulent years in charge.
Palermo began the season under Davide Ballardini who left by mutual consent in early September. He was replaced by Roberto De Zerbi who was sacked at the end of November and followed by Eugenio Corini, who resigned in January.
(Writing by Brian Homewood; editing by Richard Lough)
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