Lions defender Darren Purse headed the hosts in front in the 42nd minute and Josh McQuoid added a second two minutes later.
North End's 22nd defeat of the season was confirmed after the break as John Marquis added a third before James Henry's penalty sealed the rout.
The result lifted Millwall to within two points of sixth-placed Nottingham Forest and left Preston five points from safety with only three games remaining.
The visitors have showed signs of significant improvement in recent weeks and they threatened inside the third minute when midfielder Darren Carter hit a 25-yard shot which flew narrowly over the crossbar.
Moments later it was Millwall's turn to go close as Marquis drilled in a shot from 18 yards which Preston's on-loan Everton goalkeeper Iain Turner was equal to.
Iain Hume then saw a 20-yard shot flash just wide but Millwall went close again in the ninth minute when Liam Trotter's fierce 12-yard strike was expertly tipped around a post by Turner.
From the subsequent corner by Trotter, Henry fired goalwards from 20 yards and Turner was again on hand to tip the ball round a post.
Carter then threatened from distance again for Preston but Millwall were always dangerous in front of goal and McQuoid and Marquis both went close before the opening goal finally arrived in the 42nd minute.
Henry's inswinging corner from the left flank was met by Purse and the defender's firm header flew into the net from six yards out.
Preston were dealt another blow shortly after as on-loan Tottenham defender Bongani Khumalo had to go off injured and was replaced by youngster Bailey Wright.
The disruption seemed to affect Preston as Millwall immediately grabbed their second when McQuoid took a pass from Marquis and fired into the top left corner with a superb right-footed strike from 30 yards.
Millwall lost Trotter to injury at half-time and replaced him with Nadjim Abdou.
And Abdou was instrumental in helping Millwall get their third goal in the 54th minute.
His neat pass was met by Marquis who fired a low left-footed shot into the net from six yards.
Preston boss Brown made a double substitution on the hour, replacing strikers Chris Brown and Hume with Paul Hayes and Nathan Ellington respectively.
However, it soon got worse for Preston as Millwall made it four in the 65th minute.
Turner felled McQuoid and Henry stepped up to fire home from the penalty spot into the top right corner.
Henry went close to scoring again in the 67th minute when his 12-yard shot was well saved by Turner and then Andros Townsend fired over the bar.