Former Villarreal and Sevilla boss Marcelino Garcia Toral will take charge of Valencia, the sixth coach hired by owner Peter Lim in two years.
Marcelino has signed a two-year contract with the two-time Champions League finalists.
Interim boss Voro will remain in charge of the Spanish club for the last two games away to Espanyol on Saturday and at home to Villarreal on 21 May.
Valencia are 13th in La Liga, closer to relegation than a European spot.
They started the season with former Liverpool assistant Pako Ayestaran in charge but he was sacked with the side bottom of La Liga after losing their opening four games of the season.
Marcelino, 51, had been a candidate to replace Ayestaran.
However, league rules do not allow coaches to manage more than one club in the same season and Marcelino was deemed to have started the campaign at Villarreal, although he was sacked before their first game of the season in August.
Former Italy boss Cesare Prandelli, 59, took charge of Valencia instead but resigned after 10 games in charge.
Voro led the team to safety but has since confirmed he will leave at the end of the season.
Former Manchester United and England defender Gary Neville, 42, was sacked by Valencia after less than four months in charge in March 2016.