Rowan Vine's tenth goal of the season in the second minute and Carlos Edwards' sixth of the campaign put Town 2-0 up at the break.
And Town comfortably held on for the win despite a late fightback from the visitors.
The win ended Luton's recent run of eight consecutive league and cup defeats that had marked their worst sequence of results in more than 100 years.
Luton made two changes to the side that lost 1-0 at Plymouth in midweek. David Bell came in for Russell Perrett meaning Markus Heikkinen moved back to centre-half after his recent exploits in midfield, and Dean Morgan started the game up front in place of Warren Feeney.
Preston, who included ex-Hatter Graham Alexander in their 11, kept the same side that drew 1-1 against Coventry on Tuesday night.
After Barnsley's 2-2 draw at Leeds earlier in the day, Luton knew they needed to avoid defeat to prevent them slipping into the bottom four.
And they got off to the perfect start by opening the scoring after just 74 seconds.
A foul by Simon Whaley on Carlos Edwards by the right touchline gave Bell the chance to flight a curling free-kick into the area.
The ball went over everyone, but Steve Robinson retrieved the situation by scampering to the left and crossing for Vine who, all alone inside the penalty area, took a touch before steering the ball past the exposed Carlo Nash, left-footed from 10 yards.
Town had to defend for a period as Preston forced three corners, but it was Luton that almost scored again in the 13th minute.
Robinson, playing against his former club, started and finished the move as he played in Edwards to tee up Kevin Foley to cross for Robinson to see his eight-yard right-foot volley tipped over by Nash.
A minute later Town threatened again when Morgan's superb first-time cross from the right led to Vine having a shot blocked on the edge of the six-yard box before Ahmet Brkovic collected the rebound, turned his man and curled a left-footed effort past the far post from 10 yards.
Luton looked lively going forwards and it was no surprise when they made it 2-0 in the 19th minute.
Vine combined well to release Bell down the left and, after the ex-Rushden man's cross was half-blocked, Morgan collected the ball at the near post before beautifully creating space to drill a cross-shot across the goalmouth for Edwards to touch into the empty net at the far post.
With Preston looking anything but a table-topping team, Town roared forwards again in the 26th minute when more slick interplay saw Morgan feed Vine, who set off on a marauding 30-yard run that left Liam Chilvers for dead, before firing a left-footed effort just wide of the post from 16 yards.
After Leon Barnett and Brkovic both placed 33rd minute headers at Nash, Preston finally created an opening a minute later when David Nugent wriggled free of Barnett for the first time in the game, reached the right by-line and pulled the ball back for Tommy Miller, but his 15-yard shot was blocked by the backtracking Bell.
The second half started in sedate fashion with Luton happy to sit on their lead, but the best the Lilywhites could offer was a 20-yard Chris Sedgwick effort that flew off target just before the hour.
Luton, who saw Morgan limp off with injury, woke up and Edwards and Bell combined to set up Robinson for a cheeky 20-yard chip that Nash scrambled back to save.
Alexander blasted a 20-yard free-kick over in the 62nd minute before nervousness from Nash saw him collide with a defender when trying to field an Edwards cross in the 64th minute and Brkovic was able to fire a cross-shot to Vine who couldn't convert on the stretch at the far post.
Preston kept pushing and Sedgwick hit another long ranger just over in the 78th minute before Dean Kiely produced three superb late saves from Nugent's bullet header, substitute Danny Dicho's aerial effort and fellow substitute Brett Ormerod's close-range attempt.
It wasn't all one-way traffic though as Brkovic curled just wide from 20 yards and Bell saw a scorching effort blocked by Nash in stoppage time.