Admiral Muskwe put them ahead within two minutes and Jason McCarthy made it a comfortable lead with just a quarter of the game gone, before substitute David Wheeler wrapped things up in the closing stages.
The win, just a third on the road in the Championship, took Wycombe off the bottom for a few hours until Sheffield Wednesday beat Cardiff City, and narrowed the gap to safety to eight points with six matches left.
Rotherham remain in a better position in 22nd with games in hand too, but they have lost eight of their last 10 and produced their poorest performance of the season, especially defensively.
Story of the match
Wycombe were on their way within two minutes, when Muskwe was presented with a simple chance by Dan Barlaser's wayward header which he side-footed into the corner for his second goal for the club. It owed much to their opponents’ generosity at the back, as Rotherham felt the absence of suspended captain Richard Wood as well as the resulting switch to a four-man defence which did not pay dividends.
That said, Wycombe’s energy, desire and spirit made them more than worthy of the lead and they continued to cause the greater problems, Muskwe blasting another effort over and Anis Mehmeti finding the side netting before another gifted goal, when McCarthy was given far too much space to be found by Uche Ikpeazu and his strike deflected off Ben Wiles beyond the helpless Viktor Johansson.
There had been some opportunities for the generally unsettled home side before then, with Michael Ihiekwe sending a bullet header wide and Jack Grimmer making a crucial intervention to stop Freddie Ladapo tapping in a Michael Smith cross, but only after the second goal did they offer a consistent threat.
Jamie Lindsay, Matt Crooks and Smith all offered optimistic efforts before goalkeeper David Stockdale made his first serious intervention, a sharp double save to deny Wiles' fizzed cross and then the rebound from Lindsay, who also aimed another chance that needed to be pushed away before the break.
Paul Warne changed approach at the break with a return to a back three, while Gareth Ainsworth introduced Wheeler to have an extra man in midfield. The sum of the changes was more control for Rotherham, but it brought them no closer to a goal.
In fact they were creating far fewer chances, Lewis Wing dragging wide from the edge of the box and Angus MacDonald failing to stretch Stockdale from a little closer out, and in the end they reverted to their original formation for the final quarter of an hour.
Wing's deflected strike might have provided the spark for an unlikely comeback, but Stockdale gathered and the result was secured for his side a couple of minutes later. Adebayo Akinfenwa slipped in fellow substitute Wheeler, who calmly tucked the ball underneath Johansson to spark well-earned celebrations of joy.
Rotherham came as close as they had all half in the final, inconsequential minutes, Smith hitting the post with a header, and it was nothing but a day of frustration as their own survival bid took a brutal blow.
Chairboys have real hope
Ainsworth has been insistent all season that, no matter how big the gap between themselves and the rest of the competition got, his Wycombe side had every chance of survival and would fight until the very end.
That is turning out to be quite prophetic, with a run of 10 points in five matches – including an Easter double following Friday’s home win over Blackburn Rovers – putting them well and truly back in the mix for survival against all odds, and this victory was surely their finest of the season, as well as the most significant.
It was never going to be done the pretty way and the match was just as scrappy as could be expected of a true relegation ‘six-pointer’, but they came out with more determination, out-fought their opponents and made their openings count with some clinical finishing.
The maths still make it an uphill task, with a seven-point deficit, six games left to play and many of their rivals hitting some form as well, but they are going up it at speed and can finally see the top. Even with a tricky set of fixtures left to negotiate, nobody would dare rule Wycombe out now.
No home comfort for Millers
With matches in hand and a lot of impressive performances, even when the results have not gone in their favour, Rotherham have always looked like having a decent chance of survival, but after this performance it suddenly looks a tall order.
It was the defensive display which did the self-inflicted damage with all three goals being conceded far too easily, and though the absence of key defenders left a makeshift line flagging, individuals will also be disappointed. They actually created a good number of chances at the other end, but couldn’t stick the ball in the net in the way that Wycombe efficiently did.
If they do return to League One, their home form will be the biggest reason why. A record of four wins from 18 matches at the New York Stadium makes for truly grim reading, with no side in the division picking up fewer points on their own turf.
A massive week lies ahead, with a run of four matches in eight days beginning at Huddersfield Town on Saturday as their games in hand are crammed into the calendar. Four home fixtures in a row follow and, if they want to have any realistic hopes of staying up, they need to turn that dismal record around, as well as the faults that left them battered and bruised here.
Man of the match: David Stockdale (Wycombe)
Made some excellent saves in front of an equally solid defence to pick up a fourth clean sheet in five matches.