Long-range strikes from Abdoulaye Doucoure and Daryl Janmaat ended Southampton's unbeaten start and lifted Watford into the top four.
The goals secured a 2-0 victory for the upwardly-mobile Hornets as Saints' struggles in front of goal continued.
Doucoure pounced shortly before the break from outside the box and Janmaat hit a second-half cracker just four minutes after coming on as a substitute.
Meanwhile, shot-shy Southampton drew a blank for the third time in their four Premier League matches so far this season.
They have issues to address at the back, too, as there was again no Virgil van Dijk in the line-up.
The club captain is now building up his fitness after failing to get the move he wanted before deadline day, so fellow Dutch centre-back Wesley Hoedt was handed his debut.
The new boy was kept busy early on by the bustling Hornets striker Andre Gray, while Brazilian youngster Richarlison was proving a handful down the left.
Richarlison created the first decent opening, midway through the first half, when he evaded two defenders before seeing his shot deflected wide by Jack Stephens.
Neither goalkeeper had been forced into action until seven minutes before half-time when Southampton only half cleared a ball into their penalty area.
It fell to Doucoure 20 yards out and the French midfielder lashed a right-footed volley past Fraser Forster and into the bottom corner.
Forster did make a save moments later, at his near post to deny Richarlison, and Doucoure sidefooted narrowly over as Watford finished the half on top.
That led to boos from some of the Southampton faithful as their side trudged off - harsh given they were previously unbeaten, and it is only September.
They staged a brief revival after the interval but Sofiane Boufal sliced his shot over and Nathan Redmond hit the side-netting.
A Watford defence already hit by injuries was stretched further when Younes Kaboul and Kiko Femenia both limped off on the hour.
But rather than knocking the visitors out of their stride, the changes paid immediate dividends as o ne of the substitutes, Janmaat, expertly found the far corner from 25 yards out .
Saints boss Mauricio Pellegrino sent on Shane Long and Charlie Austin in desperate search of a goal.
But the only cheers from the home crowd were the ironic ones which greeted Southampton's first shot on target, from Cedric Soares, in stoppage time.