Deon Burton and Burton O'Brien did the damage as the struggling Yorkshire side upset the form book and handed Preston only their second league defeat in 27 league games.
Runaway Championship leaders Reading are the only other league side to have beaten Preston since September when they started their amazing run.
Wednesday produced their first win in seven and by the end the shell-shocked visitors were well beaten.
Preston could have gone ahead when they were gifted a chance by Mikkel Bischoff's fresh air clearance after 32 minutes.
He missed with a wild swing on the edge of the box and Brett Ormerod could hardly believe his luck as the ball arrived at his feet. But he dithered and Peter Gilbert and Scott Carson combined to block his hasty shot.
Chris Sedgwick twisted and turned in the area but his shot was blocked and when Sedgwick slipped a neat ball for Graham Alexander, his low shot was blocked.
Wednesday struck with their first effort of note in the 38th minute. Chris Brunt's curling corner was headed goalwards by Marcus Tudgay and Burton stole in to head past Carlo Nash.
A minute later Burton, who grabbed his first goal for the club last week, should have put further in front but his close range flick was pawed away by Nash after the Preston keeper had spilled Glenn Whelan's stinging 25-yard free-kick.
And five minutes before the break Tudgay's diving header from Brunt's cross was comfortably saved by Nash.
Six minutes into the second half Wednesday put the game beyond Preston when Tudgay's quick throw in bounced invitingly for Burton O'Brien who flicked the ball over Nash for his first goal for Wednesday since signing from Livingston last summer.
Preston pushed forward looking for a way back but Wednesday stayed in the driving seat and might have added a third goal on the break but Burton's shot was wide.