In what is fast becoming a farcical season at the Stadio Renzo Barbera, Gasperini departs by mutual consent only 15 days and two games after returning to the hotseat on February 24.
The 55-year-old was reinstated after Alberto Malesani's brief 19-day reign, which started on February 5 and comprised only three games, but a goalless draw at Torino and Sunday's 2-1 home defeat to relegation rivals Siena have persuaded former Inter Milan boss Gasperini to move on.
A statement published on palermocalcio.it read: "After a meeting between adminstrative director Giorgio Perinetti and Gian Piero Gasperini, Palermo can announce it has reached an agreement for a consensual termination of the coach's contract.
"The owner has tasked the director with assessing who should take control of the first-team squad."
Reports in Italy suggest the Rosanero will now turn to Napoli-born coach Giuseppe Sannino, who started the season in charge of the Sicilian club only to be sacked after three games.
The Neapolitan tactician would return to the Renzo Barbera almost six months after he became president Maurizio Zamparini's first casualty of the season on September 16.
Gasperini then claimed three wins from 20 games to leave the Sicilians in 19th place upon his original departure, with UEFA Cup-winning coach Malesani appointed the next day.
Malesani could not improve Palermo's fortunes, however, with three points from three draws leaving the Rosanero bottom of the table and ushering in the fleeting return of Gasperini.
Zamparini told the Corriere dello Sport early on Monday: "We won't be able to save ourselves now, it's folly to think we can do it.
"We would need a lot of luck and for our players to act as if they're men rather than baby food. I don't know what they are made of.
"I'm not giving up but the maths reads otherwise. In my 30 years in football I faced relegation twice with Venezia and on both occasions we returned to Serie A."
The first task for Gasperini's replacement is a trip to face third-placed AC Milan at the San Siro on Sunday.
Palermo are currently tied for last place with Pescara on 21 points and five points from safety.