Preston have found Crewe difficult opponents in recent meetings – they are without a win in five games against the Cheshire outfit.
The last time PNE came out on top was in August 2011 when they beat the Railwaymen 3-2 in the League Cup at Deepdale.
They left it late to do that though, North End trailing 2-1 with six minutes left.
A long-range shot from Daniel Devine brought them level, with Iain Hume heading home a 90th-minute winner.
Victory kick started their season after an opening-day league defeat to Colchester.
Phil Brown put out a mix-and-match side, youngsters Devine, Seanan Clucas and Adam Barton drafted into the starting XI.
Paul Coutts and Barry Nicholson were rested on the bench.
The way North End started proceedings gave little clue as to the drama which would be needed later on to secure them a win.
They were ahead inside three minutes thanks to an own goal from Alex defender Matt Tootle.
A left-wing cross from Paul Parry found Jamie Proctor in the box, his downward header hitting Tootle on the shin and wrong-footing goalkeeper Steve Phillips.
It needed a diving save from Iain Turner to keep the lead intact, the Preston keeper pushing a Shaun Miller shot behind.
Crewe were level in the 16th minute, Barton losing his footing in midfield and giving away possession.
The visitors broke three against two, the ball worked to Miller, whose shot struck the covering Brian McLean.
But the ball broke back into his path and Miller made no mistake with a low drive across Turner.
As Crewe got the upper hand, Bryon Moore’s shot on the turn tested Turner, good work by Ajay Leith-Smith having created the chance.
At the other end, Barton tried to atone for his earlier error with a shot from distance which travelled over the bar.
Crewe took the lead five minutes before the interval to stun Deepdale.
Nick Powell’s corner was missed by Turner as he came out to try and claim, leaving David Artell with the simple task of nodding the ball into the roof of the net.
Preston responded with Hume and Clarke Carlisle both going close to levelling the scores.
In the early moments of the second half, Hume shot over the bar and Neil Mellor’s path to goal was blocked by a sliding challenge from Lee Bell.
Phillips saved well from a Mellor shot, the striker having been picked out by McLean’s well-flighted cross.
Coutts and Danny Mayor joined the action from the bench in a bid to pep North End up.
The home side’s equaliser came in the 84th minute, centre-half Devine shooting from 25 yards.
It clipped off Mellor and flew past Phillips to the relief of the home crowd.
As extra-time loomed, Preston hit their winner.
Mayor cut inside off the left wing and delivered a fine cross into the box which Hume rose to meet and guide a header inside the far post, setting up a second-round visit to Charlton.