The Lilywhites turned the game on its head in the closing stages, coming back from 1-0 down to win 3-1.
They could have been out of sight by half-time but saw a number of chances go begging, Wednesday punishing them when Jacob Murphy broke the deadlock just before the hour.
It stayed that way until the 78th minute, that the cue for North End's substitutes to make a huge impact from the bench.
Two of them, Scott Sinclair and Jayden Stockley, combined for the equaliser, Stockley's flick sending Sinclair into the box to score.
Stockley then tucked away a wonderful finish on the turn from the edge of the box, Daniel Johnson - on as a sub - having fed him the pass.
Not to be outdone, Brad Potts completed the scoring with a great shot from the edge of the box after a 20-yard run.
PNE manager Neil said: "I think the chances we had in the first half were the five clearest we will have.
"When we didn't take advantage there is always the fear that you will concede first after being so dominant.
"That happened and what we did was show the character we have to come back and win.
"I think it just shows that in terms of the squad, everyone is desperate to try and force their way into the team and show what they can do.
"For the substitutes to make the impact they did was very pleasing."
Victory moved North End up to eighth place, three points behind Cardiff in sixth place and two shy of seventh-place Swansea.
Neil changed system for the visit to South Yorkshire, bringing in Jordan Storey for his first game since January and first league appearance since December.
Last season's young player of the year was impressive in a 3-5-2 system, operating on the right hand side of the three-man defence.
"It is not easy coming into the side but when you are a young player it is your opportunity to take," said Neil.
"An opportunity might came along because of a change of shape or the fact results haven't been going as well as you would have liked.
"When you have that opportunity a player has to come in and stamp his authority on that position."
PNE face fifth-place Nottingham Forest on Saturday at Deepdale (3pm).