The 50-year-old Spaniard has signed a two-year contract at Vicarage Road and will be assisted by Alberto Diaz and Antonio Carlavilla.
He takes over from Serbian Slavisa Jokanovic who left Watford after securing their promotion to the top flight last month as Championship runners-up.
"I'm proud to have had the chance to help put this club back where they truly deserve to be. I wish you all the best in the future," Jokanovic, who joined the club on a short-term contract in October, said on Twitter after his replacement was confirmed.
Sanchez Flores, a right back who spent most of his career at Valencia and played 15 times for Spain, coached Real Madrid's youth teams before he took charge of Getafe in 2004.
He moved back to Valencia where he achieved a third-place La Liga finish and Champions League qualification in his first year. Under his stewardship Valencia reached the Champions League quarter-finals in 2007, losing to Chelsea.
After a short spell at Benfica, Sanchez Flores took over at Atletico Madrid where he won the 2010 Europa League and later that year the European Super Cup against Inter Milan.
Sanchez Flores returned to Getafe this year following a spell in Dubai with Al Ahli, but quit after 11 games.
(Reporting by Ed Osmond; editing by Justin Palmer)
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