Nathan Elder's 29th-minute header was the difference between the two sides, but the Bees could have had more had it not been for a series of saves by Hatters goalkeeper Conrad Logan.
A miserable night for the hosts was compounded when skipper Keith Keane saw red for a foul on Charlie MacDonald five minutes from time.
The two sides had met in the Johnstone's Paint Trophy in October when Luton had battled back from 2-0 down to win on penalties.
And, just as in the previous clash, the Bees started the better and almost took the lead in the eighth minute when MacDonald profited from Ian Roper's slip only to be denied by home goalkeeper Logan's smart block.
Luton responded four minutes later with an angled drive from Jake Howells that was saved by Ben Hamer at his near post just moments after Alan Bennett had cleared Asa Hall's cross-shot off the line.
Hamer comfortably saved another angled drive, this time from Kevin Gallen in the 23rd minute, before MacDonald again found space 60 seconds later only to flash his 20-yard shot past the post after Hamer's long clearance.
The opening goal eventually arrived in the 29th minute when Dean Bowditch, on-loan from Ipswich, did superbly well to bring down Ryan Dickson's driven free-kick before crossing for Elder to nod home his sixth of the season from six yards.
Luton had been poor in the first half but showed signs of improvement after the break. In a two-minute spell on the hour firstly Paul McVeigh had an 18-yard shot hacked off the line by Karleigh Osborne before Hall sent a 22-yard scorcher just over the bar.
Brentford though almost doubled their lead in the 63rd minute when MacDonald teed up Bowditch to fire in a low 25-yard drive that Logan did superbly well to tip around the post at full stretch.
Two minutes later Roper was in the right place to block a close-range effort from Elder that looked certain to register his second of the evening after Bowditch's cross.
After a brief period of Luton pressure, the Bees then threatened again in the 71st minute when Dickson's marauding run from left-back ended with a shot that deflected off Elder only to somehow be kept out by Logan.
Seconds later Elder found himself clear through on goal only to lift the ball over the bar.
An action-packed second period continued with the hosts almost levelling when Hamer held on to Hall's ten-yard header after Jake Howells' corner.
Elder then saw a header cleared off the line in the 79th minute before McVeigh's 30-yarder was tipped aside by Hamer five minutes later.
Any hopes Luton had of salvaging a point disappeared when Keane was controversially sent off five minutes from time for bringing down MacDonald, even though the Hatters appeared to have covering players.