They trailed the Seasiders at half-time but roared back to score three goals in 22 minutes.
Chris Brown scored twice, either side of a Neil Mellor header.
Mellor enjoyed scoring in the derby clash so much that he ended up jumping into the away stand to celebrate with members of his family.
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It was a much-needed three points for North End who had travelled down the M55 having won only two of their previous 10 matches.
They were backed by 1,700 PNE fans at the game, with another 1,400 watching on the big screen at Deepdale.
In the first half, the visitors looked off-colour and it was Blackpool who had much the better of it.
Mellor had the ball in the net in the third minute but an infringement saw refeeree Mike Dean disallow it.
North End goalkeeper Andrew Lonergan parried a free-kick from Adam Hammill and blocked Gary Taylor-Fletcher’s follow-up.
Hammill gave the hosts a 10th-minute lead, latching on to a pass from Alan Gow to rifle a right-foot shot into the top corner.
With Liverpool loan man Hammill going to have a couple more chances, there was plenty for Lilywhites manager Alan Irvine to sort out during the interval.
Whatever the Scot said to his players and tweaked tactically, worked a treat. Paul McKenna was dropped a little deeper in midfield to cut off the threat to targetman Ben Burgess.
And all-round, Preston just looked more confident.
Mellor pulled a shot just wide after a Richard Chaplow pass before strike partner Brown equalised in the 55th minute.
Brown played his part in the build-up, getting the ball in midfield and rolling a pass down the left channel to find Ross Wallace.
The winger made as if to step inside Shaun Barker but instead moved the ball on to his left foot, whipping over a cross which Brown – by now in the box – headed home from six yards.
Wallace, Brown and Chaplow were all involved in the build-up to PNE taking the lead in the 68th minute.
Chaplow’s pass was chased by the overlapping Callum Davidson down the left.
Davidson stood up a cross to the far post where Mellor rose between two defenders to guide a header into the net.
He set off on a run towards the Preston supporters down the side of the pitch before hurdling the advertising boards to join in the celebrations.
North End weren’t finished there, making it 3-1 with 77 minutes on the clock.
Sean St Ledger’s pass found Mellor down the right, the striker staying on his feet despite a sliding challenge from a Blackpool defender.
His low ball travelled across the box and beyond the far post where it was picked up by Wallace.
He turned it back into the middle where Brown took a touch and side-footed a shot into the net.
Brown was to remark later: “It was like two different Preston sides out there, one in the first half and one in the second.”
It was North End’s first win at Blackpool for 16 years, since a 3-2 victory in 1992.
Gathering three points by the seaside formed part of a run of just two defeats in 11 league games.
That run helped push the Lilywhites up the table and mount a play-off push.