Di Francesco departed on Tuesday (AEST), 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," said a club statement.
"The president and his colleagues thank Di Francesco and his staff for their work."
Di Francesco's predecessor Marco Giampaolo is also struggling in Serie A this season with his AC Milan side 13th despite a weekend win at Genoa.