Di Francesco departed on Monday, two days after a 2-0 defeat away to Hellas Verona made it six defeats out of seven league games.
Samp handed Di Francesco a three-year deal in June, with the coach returning to the dugout four months after being let go by Roma.
"The president Massimo Ferrero and Sampdoria announce they have reached a mutual agreement with Eusebio Di Francesco and his technical staff to end their professional relationship," a club statement read.
"The president and his colleagues thank Di Francesco and his staff for their work."
The club's sole Serie A win of the season came at home against Torino as Manolo Gabbiadini hit the only goal of the game.
It was the only clean sheet that Sampdoria have kept this season and one of just four goals that have been scored in the league.
Their struggles come as a surprise following their impressive ninth-placed finish in the table last term, a season in which they were the fifth-highest scorers in the division.
That was, in part, thanks to the blistering form of veteran striker Fabio Quagliarella, who finished the campaign as the top scorer in Serie A - ahead of even Juventus superstar Cristiano Ronaldo - with a whopping 26 goals in 37 league appearances.
However, the forward, who is now 36 years old, has only managed one goal from his six league games so far - a meaningless consolation in a 4-1 defeat against Sassuolo.
As a result, the club may simply wait and re-hire the manager who got the team performing so well last term, if he is indeed sacked by the Rossoneri board.
Milan have won three and lost three of their seven Serie A games, and have scored just six times so far in the Italian top flight.
Despite winning at the weekend, it appears likely that the club will use the international break to cut their losses and find a replacement.