The Dragons capitalised on the absence of fifteen internationals from the Ospreys line-up to secure a 21-16 victory at Liberty Stadium on Saturday.
It was the visitors first away victory at the Ospreys in seven years of regional rugby, taking the Magners League derby by two tries to one.
Number eight Toby Faletau and scrum-half Wayne Evans scored the key tries for the Dragons, who took advantage of the Ospreys being without 16 players.
Gareth Owen scored the Ospreys try, who had the consolation of a losing bonus point.
The Dragons held a deserved 8-3 lead at the interval having shaded possession and territory in the first half.
The highlight for the Gwent side was the 38th minute try from Faletau, the Welsh qualified loose forward, who battled his way past three would-be tacklers to score in the left corner.
It was the best moment of a largely ordinary first 40 minutes which was played out in heavy rain.
The Dragons had much the better of the territorial advantage with two line-outs in the Ospreys 22 before Jason Tovey, who controlled things from fly-half kicking his side into a 3-0 lead with a 13th minute penalty goal after the Ospreys had been caught offside.
The Ospreys had the best chance of scoring the opening try when former Dragons wing Richard Fussell went close down the left.
It was a lead the Dragons held on to until the 37th minute when Dai Flanagan made it 3-3 from a penalty kick after English referee Dave Pearson had blown up for crossing.
But a minute later Faletau was over after Gavin Thomas had made the initial break into the Ospreys 22.
To make matters worse for the home side Flanagan missed a relatively easy penalty in the second minute of injury-time.
But the Ospreys more than made up for it at the start of the second half with Owen going over for a try after only two minutes after Fussell had made a break up the right wing and passed inside to the full-back.
The Ospreys only held the lead for two minutes before Jason Tovey converted his second penalty.
Flanagan missed a penalty on 53 minutes but was successful five minutes later with another attempt as the Ospreys went back into the lead at 13-11.
But again the Ospreys' advantage was short-lived as the Dragons went in for their second try. A good build-up involving Thomas, Tom Willis and James Leadbeater ended with Wayne Evans nipping in for the score down the blindside.
Owen and Tovey traded penalties before the Dragons held out for a famous victory.
Pen: Flanagan 2, Owen
Tries: Faletau, Evans
Pen: Tovey 3
Ospreys: 15 Gareth Owen, 14 Nikki Walker, 13 Sonny Parker, 12 Ashley Beck, 11 Richard Fussell, 10 Dai Flanagan, 9 Jamie Nutbrown, 8 Jerry Collins (c), 7 Marty Holah, 6 Tom Smith, 5 Ian Evans, 4 Andy Lloyd, 3 Craig Mitchell, 2 Mefin Davies, 1 Ryan Bevington.
Replacements: 16 Richard Hibbard, 17 Duncan Jones, 18 Cai Griffiths, 19 Conor McInerney, 20 Justin Tipuric, 21 Rhys Webb, 22 Tom Isaacs, 23 Barry Davies,
Dragons: 15 Pat Leach, 14 Adam Hughes, 13 Tom Riley, 12 Ashley Smith, 11 Nathan Brew, 10 Jason Tovey, 9 Wayne Evans, 8 Toby Faletau, 7 Gavin Thomas, 6 Andrew Coombs, 5 Rob Sidoli, 4 Luke Charteris (c) 3 Nigel Hall, 2 Steve Jones, 1 Phil Price.
Replacements: 16 Tom Willis, 17 Hugh Gustafson, 18 Pat Palmer, 19 Scott Morgan, 20 Robin Sowden-Taylor, 21 Shaun Connor, 22 James Leadbeater, 23 Matthew Jones
Referee: Dave Pearson (RFU)