The four-times African Footballer of the Year, who moved to Everton in August and scored four goals in 20 appearances, has signed a two and a half year contract with Sampdoria.
"We thank Samuel for his efforts and for bringing his know-how to the team," manager Roberto Martinez told the club website. "On behalf of all Evertonians we wish him well for the next chapter in his career."
Eto'o, 33, helped Barcelona win the Champions League in 2009 and lifted the trophy again as an Inter Milan player the following year.
He moved to Russian club Anzhi Makhachkala in 2011 in a deal that reportedly made him the highest paid footballer in the world before joining Chelsea in 2013.
(Reporting by Ed Osmond, editing by Tony Jimenez)
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