Having been replaced at the top of the table by Leinster overnight the Welsh outfit narrowed the gap to just one point with a gritty performance that frustrated Munster who had to settle for a losing bonus point.
Huw Bennett, Ryan Bevington, Dan Biggar, Ian Evans, Ryan Jones, Justin Tipuric and Shane Williams were all absent on international duty but second-half scores from Richard Fussell and Rhys Webb earned them a famous victory.
Munster head coach Tony McGahan also rung the changes for the away side as internationals Ronan O'Gara, Conor Murray and Paul O'Connell all had to settle for a place on the bench at the Liberty Stadium.
The Red Army have been in good form of late with three wins on the bounce and they started brightly and should have taken the lead, but the wayward boot of fly-half Ian Keatley who missed two penalties in the first ten minutes.
Not long after that Munster lost hooker Damian Varley to the sin bin and on 22 minutes Ospreys hit the front when stand-in fly half Matthew Morgan slotted over a penalty.
But three minutes later, having been restored to their full compliment, Munster were level as Keatley's misfiring boot finally honed in on its target to make it 3-3.
Just before the half hour Munster were in front as Doug Howlett glided over for the first try of the game, Keatley adding the extras to put the Red Army in a strong position to avenge their defeat from back in October.
A second penalty from Matthew Morgan reduced Ospreys' arrears to 10-6 at the break and they came firing out of the blocks after the interval in a five minute spell that effectively sealed the win.
Richard Fussell piled over in the 45th minute to put the Ospreys 11-10 ahead while Morgan failed to add the extras and then scrum-half Rhys Webb, making his 50th career appearance for the Ospreys, darted over, Morgan again failing with the conversion.
That flurry forced McGahan's hand and the cavalry soon arrived in the form of O'Connell, Murray and O'Gara and the fly-half added a penalty in the 63rd minute to reduce their arrears to 16-13.
But Morgan then added a penalty of his own to push the lead back out to six points in the 67th minute before Munster set up camp in the Ospreys half in search of a winning try.
A succession of scrums on the Ospreys five metre line with ten minutes to go pushed the Welsh pack to the limit but the front row held out and eventually earned a penalty to relieve the pressure.
But it wasn't long before Munster were back on the attack as almost the entirety of the last ten minutes was played in the Ospreys 22 but a final lineout was overthrown and Tommy Bowe booted the ball into the stands to seal what could prove to be a crucial victory.
|Ospreys Score Card|
|Munster Rugby Score Card|