A David Nugent strike seven minutes before the interval and a fortunate Richard Cresswell effort in the final minute left Derby County with a mountain to climb in the Pride Park return.
The game started badly for the Rams when Michael Johnson was stretched off after just five minutes to be replaced by Pablo Mills.
Two minutes later Cresswell saw a header saved by Lee Camp after an inch-perfect cross from the dangerous Eddie Lewis on the left wing.
Cresswell then fired wide after again being played in by Lewis, before Paul McKenna saw a 15-yard effort held by Camp.
Billy Davies' side finally got the reward their pressure deserved after 38 minutes.
Lilywhites skipper Chris Lucketti played a long ball which was headed down by Cresswell and flicked on by Chris Sedgwick to Nugent. The striker ran on before lifting the ball with the outside of his right foot over the keeper and into the bottom left hand corner of the net.
Derby rallied after the break and Morten Bisgaard fired narrowly wide from 20 yards, before setting up Mo Konjic to head wide.
Richard Jackson then saw a deflected shot saved by Carlo Nash as the visitors threatened to level.
However, Preston found a fortunate hammer blow in the final minute when a Konjic clearance hit Patrick Agyemang and deflected off Cresswell, before dribbling past the wrong-footed Camp to put North End in complete control of the tie.