year-old Italian, who has also managed Sampdoria and Napoli, has signed a three-year contract at Vicarage Road.
Spaniard Flores left after less than a year with the Premier League side.
Watford finished 13th in a season where they also lost in the FA Cup semi-finals to Crystal Palace.
Mazzarri is the Hornets’ eighth manager in the past four years.
Watford’s chief executive Scott Duxbury told the club’s official website: “Walter has been the target of a number of approaches for his services, so we’re delighted to secure him as head coach here at Watford.
“We’re thoroughly looking forward to working with such a highly regarded coach, with the progress and development of the club always remaining the highest priority.”