The Owls' hoodoo sign over QPR continued, as Brian Laws' men came from behind to clinch a crucial victory in their quest to pull away from the Championship drop-zone.
The 2-1 defeat, which leaves the R's just six clear of safety, means Rangers have now failed to beat Sheffield Wednesday, home or away, since our promotion party at Hillsborough four years ago.
Damien Delaney gave Luigi De Canio's men a dream start with his first goal in QPR colours in the 15th minute, only for Wednesday to hit back on the stroke of half-time courtesy of Graham Kavanagh.
And when Lee Camp was penalised for sending Sean McAllister to ground six minutes into the second half, substitute Deon Burton made no mistake from the spot to complete an unlikely turnaround.
Hogan Ephraim saw red late on for raising his arms in the direction of Franck Songo'o, as the R's day went from bad to worse.
De Canio made two changes from the midweek draw against Coventry City.
Damion Stewart and Dexter Blackstock returned to the starting XI, at the expense of Fitz Hall and Ephraim respectively.
Midfield general Gavin Mahon was named amongst the substitutes, after a spell on the sidelines with a medial ligament injury.
Wednesday boss Laws handed loan signing Franck Songo'o his first Owls start, but there was no place in the match-day squad for former R's loanee Ben Sahar (hamstring).
Owls front-man Enoch Showunmi drilled the ball high and wide in the opening exchanges, while at the other end, Rowan Vine thrashed Akos Buzsaky's clever free-kick high and wide.
Vine made amends on the quarter hour though, laying the ball on a plate for the on-rushing Delaney, who applied the simplest of finishes from the edge of the six-yard box to hand the R's a deserved lead.
Having silenced the Hillsborough crowd, Rangers went in search of a second, with Blackstock unlucky to see his fearsome strike drift inches wide of the post midway through the half.
Delaney was proving a constant threat to the Wednesday rearguard and when he broke through again two minutes later, only the foot of the post saved Laws' men from falling further behind as Agyemang turned Mark Beevers on a sixpence before firing the ball against the woodwork.
With jeers ringing in their ears, Wednesday were fortunate not to concede a second goal 10 minutes before the break.
Vine's jinking run concluded with him letting fly from the edge of the 18-yard box, but with Lee Grant seemingly beaten, the ball faded just over the crossbar.
Sensing his side were in danger of capitulating altogether, Laws made a double substitution in the 40th minute, with Burton and McAllister replacing the unlucky Showunmi and Ronnie Wallwork.
It proved to be a tactical masterstroke from Laws, who saw his side draw level in the first minute of added time, when Songo'o's chipped through ball found Kavanagh, who deftly headed the ball over the exposed Camp from 10-yards.
It was the first goal Rangers had conceded in 327 minutes of Championship action and the timing would've angered De Canio, who had seen his side totally orchestrate proceedings for the previous 45 minutes.
Undeterred, Rangers started the second period on the front foot. Vine's fine sole run resulted in him pulling the ball back from the by-line to Blackstock, who was only denied by a stunning parry from Grant at his near post.
But disaster struck seconds later when Camp was adjudged to have sent McAllister sprawling to ground inside the box and Burton stepped up to send the R's keeper the wrong way from the spot.
Wednesday were rampant by now and with Burton and Songo'o in full flow, the R's struggled to maintain their free-flowing hosts.
Kavanagh planted a free-kick just wide of Camp's left hand post, before De Canio made two changes in as many minutes, introducing Ephraim and Mahon to the fray.
Blackstock was denied again by Grant midway through the second half, when his glancing header from Delaney's cross was well gathered by the Owls custodian.
At the other end, Camp denied Kavanagh with a stunning full-stretch save, before Ephraim was given his marching orders for raising his arms at Songo'o.
Sheffield Wednesday: Grant, Hinds, Kavanagh, Tudgay, Beevers, Wood, Small (O'Brien 90), Showumni (Burton 40), Spurr, Wallwork (McAllister 40), Songo'o.
Subs: Boden, Burch.
Scorers: Kavanagh 45, Burton 52 (pen)
Bookings: Tudgay 82
QPR: Camp, Delaney, Stewart, Mancienne, Blackstock, Buzsaky (Balanta 75), Rowlands, Connolly, Agyemang, Vine (Ephraim 63), Leigertwood (Mahon 65).
Subs: Pickens, Rehman.
Scorers: Delaney 15
Bookings: Stewart 71, Delaney 83
Red Cards: Ephraim 92
Referee: Mr N Swarbrick
Attendance: 18, 555
