The coach joins on a one-year deal after considerable success with Portuguese club Rio Ave, with a return to Champions League football with the La Liga side his goal
The Liga giants reached the Europa League semi-finals and finished eighth under Pizzi, but new owner Peter Lim surprisingly opted for a fresh face in the dugout at Mestalla ahead of next season.
Former Porto and Deportivo La Coruna goalkeeper Nuno was immediately rumoured to be in the running for the Valencia job and the club confirmed his hiring on Thursday, with a one-year deal agreed and the option to extend it should they secure a top-four finish in La Liga next term.
A statement on the club's website read: "Valencia have reached an agreement for the signing of Nuno Espirito Santo until June 30, 2015, with the possibility of a renewal subject to seasonal sporting achievements under the Portuguese coach.
"The 40-year-old will be presented on Friday at the Ciudad Deportiva de Paterna at 12:00CET."
Nuno, who won the Champions League with Porto under Jose Mourinho, helped Rio Ave qualify for the 2014-15 Europa League after reaching both of Portugal's domestic cup finals in his second season in charge.
He will be the first Portuguese coach that Valencia have appointed in their 95-year history.