The popular striker, fresh from signing an extended contract on improved terms at Vicarage Road, replaced the man he had been left out for - Nathan Ellington - and was in the right place with nine minutes remaining to convert Lloyd Doyley's low centre after he had combined to good effect with Tommy Smith.
That swung a rollercoaster game firmly back in the home side's favour and they made their momentum count two minutes into injury time.
Southampton failed to properly deal with either on-loan signing Adam Johnson's initial set-piece or Gavin Mahon's follow-up shot and, following a game of pinball in the area, Henderson turned to sink the Saints from close range.
After an opening 45 minutes that Watford had dominated for the first part and then Southampton had assumed control of, it was the Hornets who made the breakthrough three minutes before the break.
Kelvin Davis, who had done well up to that point, dealt poorly with a Jordan Stewart set-piece and Smith resisted the temptation to go to ground in the penalty area, instead riding a challenge before standing up an inviting cross to the back post which Dan Shittu powered home to net his first of the campaign.
Yet the visitors, who had almost scored when Mart Poom diverted a deflected header from team-mate Lee Williamson onto his near post, were back on terms before the interval.
While Marlon King was turning to moan at the assistant about a decision that had not gone Watford's way, Youssef Safri had picked out Doyley, whose defence-splitting pass had found Grzegorz Rasiak, and the big Pole slid the ball wide of Poom to make it 1-1.
Both King and Ellington could have scored in the early stages of the second half, but Saints looked like they might be on course for an unlikely win when they took the lead after 70 minutes through Nathan Dyer's delightful curling shot.
However, those dreams of victory were to be dashed by a side who showed the character that was a hallmark of their promotion to the top-flight two seasons ago.
And, on this evidence, a quick return to the promised land could well be on the cards.