With just seven minutes on the clock Danny Hylton converted from the spot after Bevis Mugabi was adjudged to have fouled strike partner Isaac Vassell in the box.
The Hatters doubled their lead on 31 minutes when a perfectly executed counter saw Hylton bag his 22nd goal of the season, adding to a difficult afternoon.
With a cushion at the break the visitors added a third 10 minutes after the restart courtesy of Glen Rea’s header, before Pelly-Ruddock Mpanzu rounded off the scoring late on.
Darren Way made one change to the side that drew 0-0 with play-off chasing Mansfield Town in midweek.
A late withdrawal from the squad on Tuesday night, Jean-Louis Akpa Akpro recovered in time to start upfront alongside Francois Zoko, forcing Shayon Harrison to the bench.
Having come away from Kenilworth Road with a point back in August, the Glovers started with the same diamond 4-4-2 formation exercised in Bedfordshire.
Matching the Hatters tactically, it was an even start to proceedings before the game burst into life just past the five-minute mark.
Vassell drove into the box forcing Mugabi into a sliding challenge, and despite winning the ball referee Kevin Johnson felt the young defender took the man first and pointed to the spot.
With boos echoing around Huish Park the potent Hylton nonchalantly chipped the penalty down the middle to give the visitors an early lead.
Now winning, Luton were keen to capitalise on the home side’s frustrations towards the officials and almost did so from a Jordan Cook corner.
The midfielder’s in-swinging cross was met powerfully by Rea and despite beating Artur Krysiak, Liam Shephard was on hand to clear off the line.
Nathan Jones’ side were certainly a threat from set-pieces in the first-half, and with 20 minutes on the clock another Cook corner ended with Scott Cuthbert blasting over from inside the box.
Ironically, the Glovers fell two behind after a spell of set-piece pressure of their own.
After Francois Zoko couldn’t scramble a Dolan corner past Matt Macey, Luton launched a rapid counter-attack ending with Hylton coolly rounding Krysiak and netting his eighth goal in seven games.
Now facing an uphill battle, Way’s side enjoyed the lion share of possession as the half drew to a close, but couldn’t test the visiting ‘keeper.
With chances few and far between in the first 45 minutes it took Town just four minutes to trouble Macey’s goal after the break.
Ben Whitfield’s dangerous corner was met by the diving head of Akpa Akpro, but the striker’s effort flew wide of the target.
Despite the score line it was a positive start to the half by the hosts, as just a minute later top scorer Zoko fired into the arms of the Luton stopper following a neat turn.
Although Way’s side began the half encouragingly, the result was put beyond doubt on 55 minutes from another Luton set-piece.
Alan Sheehan’s deep free-kick picked out Glen Rea at the back post, with the defender able to loop a header back across goal and over Krysiak to all but end any hopes of a comeback.
With goals at a premium, Tom Eaves and Shayon Harrison were introduced, with the latter almost making an immediate impact.
The spurs loanee turned Ryan Dickson’s low cross towards the bottom corner only for Macey to pull out a fine stop to push it around the post, as it looked increasingly like not being Yeovil’s day.
That notion was proven when the Hatters made it 4-0 in the closing stages, as Mpanzu cut in from the left before squeezing a low drive under Krysiak, rounding off a disappointing afternoon for the hosts.
In the final few minutes Brandon Goodship had a shot saved by Macey, but it couldn’t stop the Glovers slumping to a first home defeat in five matches, in turn prolonging Town’s search for a much-needed win.
Yeovil Town: Krysiak; Shephard, Mugabi, Lacey, Dickson; Lawless, Dawson, Dolan (Goodship 82’), Whitfield (Harrison 62’); Zoko, Akpa Akpro (Eaves 67’).
Bookings: Dawson 35’, Lawless 58’
Subs not used: Maddison, James, Butcher, Sowunmi.
Luton Town: Macey; O’Donnell, Cuthbert, Rea, Sheehan; Mpanzu, Smith, Gray (Potts 66’), Cook; Hylton (Marriott 76’), Vassell (Palmer 68’).
Bookings: Smith 44’
Subs not used: Moore, Mullins, D’Ath, Justin.