Pizzi, a striker at Valencia during the 1993-94 season, will replace Miroslav Djukic, who lost his job earlier this month.
A statement from the La Liga side read: "Valencia CF have closed a deal with Juan Antonio Pizzi to make the Argentine the new manager of the club.
"Pizzi comes to Mestalla fresh from winning the Torneo Clausura in his homeland with San Lorenzo de Almagro.
"He will be joined at Valencia CF by fitness coach Alejandro Richino and assistant Manuel Suarez."
Valencia have lost three of their last five top-flight matches, including a 3-2 defeat against Real Madrid on Sunday, and sit 11th in the table.
Pizzi's first game in charge will be on January 4 when his side host Levante.
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