Czech Republic striker Vydra, signed on loan by Gianfranco Zola from Italian side Udinese in the summer, fired home in time added on at the end of the first half and struck his second in the 83rd minute to ensure Watford consolidated their play-off place.
Scott McDonald headed home a consolation for Boro in the third minute of stoppage time.
Spanish goalkeeper Manuel Almunia was back following a hamstring injury to skipper Watford, while Cristian Battocchio made his second start of the season and fellow midfielder Almen Abdi also returned.
Watford saw enough of the ball, but by the time Almunia had turned away Ledesma's angled shot in the 42nd minute, the visitors had failed to muster a single effort on goal.
But Vydra pounced on a loose ball in first-half injury time before firing a drilled left-footed shot into the bottom corner.
Substitute midfielder Merouane Zemmama was then sent on for Emmanuel Ledesma as Mowbray looked to salvage a point, but Watford went close to extending their lead when Vydra's close-range effort forced a fine reflex save from Jason Steele.
But Steele was helpless when Vydra steered home his second in the 83rd minute, taking Abdi's cross from the left in his stride to bury another finish into the bottom corner.
McDonald headed home Reach's cross in the 93rd minute, but it was a mere consolation, and it means Watford have now won seven times on the road this season.
- Sports & Recreation
- Manuel Almunia