The 22-year-old defender arrives at the Mestalla on a five-year contract, and is set to undergo a medical on Thursday.
"Valencia CF have reached an agreement with UC Sampdoria for the transfer of German international centre-back, Shkodran Mustafi," the La Liga club said in a statement.
Having joined Everton from Hamburg as a youngster, Mustafi made his one and only first-team appearance for the Merseyside club as a substitute in a 1-0 UEFA Europa League defeat to BATE in 2009.
In 2012, Mustafi moved to Serie A with Sampdoria, where his career began to flourish.
He eventually became a first-team regular at the Italian club, making 33 top-flight appearances last term, chipping in with one goal.
Those performances caught the eye of national team coach Joachim Low and Mustafi made his international debut earlier this year before playing three times during Germany's successful World Cup campaign.
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