Karl Duguid and Luke Summerfield fired Pymouth to the win they needed to rise off the foot of the table as Watford fell to a first home loss this season.
Duguid's classy finish capped a superb move to put Argyle on course for a first league win of the season.
And Summerfield sealed the points in the 72nd minute from the penalty spot after Hornets captain Jay DeMerit had inexplicably handled.
John-Joe O'Toole scored a late goal but it was not enough for the hosts.
Watford manager Adrian Boothroyd: "If you were to say we are in for a long, hard winter I would have to get my coat and agree with you. We've got one recognised centre-forward at the club.
"With our best 11 players on the pitch we'll go toe-to-toe with anyone but Plymouth made seven changes and if I made seven changes I would have had the physio at right-back.
"I'm going to have a chat with the chairman and see what's available because it's a lot to ask for this squad to play as many games as we have got coming up."
Plymouth manager Paul Sturrock: "We are not in any way out of the mire. This is going to be an uphill tussle all season.
"We have got to realise that we are fighting for our lives in this division between now and the end of the season.
"There will be a lot of nights like this between now and May."
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