The 41-year-old Spaniard, who replaced Vladimir Ivic in December when Watford were in the second-tier Championship and guided them to automatic promotion, became the first Premier League manager to lose his job this season.
Watford have struggled on their top-flight return, suffering four defeats and are only four points above the relegation zone.
A club statement on Sunday read: "The board feels recent performances strongly indicate a negative trend at a time when team cohesion should be visibly improving.
"The Hornets will always be grateful to Xisco for the part he played in securing last season's promotion and wish him well for his future career in football.
"No further club comment will be available until the imminent announcement of a new head coach."
Under the ownership of the Pozzo family, Watford are now in search of their 14th permanent manager 10 years.
Xisco's last match in charge was Saturday's 1-0 defeat at Leeds United.