It brings an end to Giampaolo's second spell at the club, having also been in charge between 2016 and 2019, but after recording just two points from their first eight games of the Serie A season, the 55 year-old has departed again.
After returning in January to replace Roberto D'Aversa, Giampaolo took charge of 24 Serie A games, winning five, drawing three and losing 16.
The former Milan and Torino manager was finally relieved of his duties after goals from Matteo Pessina, Gianluca Caprari and Stefano Sensi condemned Samp to a hefty loss to newly-promoted Monza at the Luigi Ferraris Stadium.
A statement on the club's website read: "U.C. Sampdoria have announced that they have relieved coach Marco Giampaolo of his duties.
"The club would like to thank Marco and his staff for the dedication and professionalism they showed while working for Sampdoria."
Sampdoria travels to Bologna on Sunday (AEST).