Danish striker Emil Riis netted both, the first a stunning 27th-minute strike into the top corner and the second a penalty in added time at the end of the opening half, to inflict a first defeat on the Town since leaders Bournemouth beat them on September 25th.
Manager Nathan Jones made three changes to the side that beat Hull last week to move into the play-off places, with Cameron Jerome starting up-front in place of Elijah Adebayo, who missed out through injury, as did Luke Berry, who was replaced in the heart of midfield by Pelly-Ruddock Mpanzu.
Returning from suspension, Kal Naismith started on the left side of a back three, with Fred Onyedinma amongst the substitutes, while Danny Hylton was named on the bench for the first time since rescuing a late point against Bristol City.
After a fairly even and uneventful opening period, Preston fired the first warning shot on the Town goal with 18 minutes on the clock, although Tom Barkhuizen's effort from just outside the area flew high over the bar.
It was for a foul on the Preston wideman that Amari'i Bell became the first player to be shown yellow by referee Dean Whitestone, and by the 27th minute the hosts had the lead, Emil Riis arrowing a shot from a tight angle outside the right edge of the area inside the top corner of Simon Sluga's net.
Preston wasted another chance when Riis chose not to shoot, with Sluga off his line, but lay the ball back for Sean Maguire to have a go, only for Jordan Clark to get a block in.
Tom Lockyer and home midfielder Alan Browne both went into the book for their roles in sparking a melee after the Wales international had been fouled by the Preston captain, before James Bree's free-kick presented Glen Rea with the Hatters' first chance, Daniel Iversen saving the midfielder's header before climbing back to his feet to repel Naismith's follow-up.
The hosts extended their lead three minutes into first-half injury-time, when Riis netted his second goal, from the penalty spot, after Sonny Bradley had been penalised for a foul on Ali McCann.
Jones introduced Henri Lansbury and Admiral Muske at the break, for Rea and Bradley, and it was former Leicester youngster Muskwe who almost got the Town back in business within two minutes of the restart, Iversen flying across his line to turn his 20-yard volley behind for a corner.
Jerome flicked a Cornick long throw on moments later, but Preston managed to clear from inside their own six-yard box with no Town forward gambling at the far post, before exactly the same thing happened - this time with Naismith winning the initial header - on 57 minutes.
The Hatters were playing much more front-footed football, but it was Preston who had the next chance, Riis spurning the opportunity of a hat-trick just before the hour mark, firing wide of Sluga's near post after stealing a march on Bell.
Sluga made two good saves in the 65th minute, first to block Barhuizen's close range effort, then to tip over Patrick Bauer's towering header from the resulting corner.
Jones made his third and final regulation change with 20 minutes left, bringing on Onyedinma for Cornick, but within seconds it was Preston posing problems again, Naismith having to block bravely to keep a Josh Earl shot out, moments before Riis headed over the bar after meeting Barkhuizen's cross from the right.
The Hatters pushed to try to find a way back in, Naismith bringing a fine save out of Iversen with a long-range shot and Onyedinma headed narrowly wide, but ultimately couldn't penetrate a strong Preston backline and head into Tuesday's live TV game with Middlesbrough tenth place in the table.
Goals:
Preston: Riis 27, 45+3 (pen)
Attendance: 11,059 (989 Luton fans)
