The Hornets, who were well beaten at Burnley last time out, bounced back from their five-game winless run to strengthen their grip on third place thanks to three goals in the space of 20 minutes.
However Southampton, showing seven changes form the team which lost at Coventry City last week, perhaps predictably made the better start with their new manager looking on.
But the home side's defensive organisation saw them cope well with an awkward opening spell and they never looked back from the moment Darius Henderson headed them in front just before the half-hour mark.
The former Gillingham striker, making his first start in almost two months following an injury lay-off, was picked out by a pin-point Paul Devlin cross and easily beat his marker to head a straightforward chance past Paul Smith.
The Hornets were firmly in control five minutes before the interval when the Saints defence failed to deal with an Anthony McNamee free-kick and Malky Mackay headed down for the unmarked Clarke Carlisle to slot home from inside the six-yard area.
Southampton might have given themselves hope had Brett Ormerod done better with a good chance just before the interval, and they were made to rue that miss within two minutes of the restart when Watford effectively wrapped up the points.
McNamee's free-kick again caused them problems and this time Henderson touched the ball on and the luckless Tomasz Hajto, on as a half-time substitute, diverted the ball past his keeper with his first touch.
The third goal put the home side firmly in control although they were fortunate not to concede during a remarkable sequence of events on the hour.
After Ben Foster had pushed a rising Theo Walcott drive in the air the keeper did well to deny Ormerod's follow-up effort. Nathan Dyer then saw his close-range shot blocked only for the ball to break to the young winger again who managed to engineer an acrobatic overhead kick that rebounded to safety off the top of the crossbar.
After that Watford were largely content to take the sting out of the game with one eye perhaps already on Wednesday night's trip to Millwall, but they could have made it four when substitute striker Joel Grant glanced another good McNamee delivery wide of the target.