Luton had star striker Steven Howard sent off after only 18 minutes for a blatant elbow on defender Michael Turner. Brentford bossed the game from start to finish and won through goals from Deon Burton in the first half and then Ben May in the second.
Burton's goal came after 41 minutes when he chested down a long kick from goalkeeper Stuart Nelson and cleverly turned two defenders before firing home left-footed.
May then finished off a flowing move by turning home a Kevin O'Connor cross from close range on 62 minutes. Brentford created a string of other chances and could have rattled in several more goals as Luton struggled to contain them.
Stuart Talbot hit the crossbar after 55 minutes following a quick break superbly engineered by May.
Turner and May also went close while O'Connor was denied by a superb save from keeper Marlon Beresford.
Beresford was comfortably Luton's best player on an otherwise disappointing night for the Hatters. He also denied May with a miraculous shot from close range.
In the end Luton were well beaten and Bees boss Martin Allen could not hide his excitement.
He said: "After the game at Hinckley, the players sat in the dressing room and their heads were as low as they could be.
"It was not the performance I wanted and the players were disappointed not to perform on national television.
"For this game I told them the nation wasn't watching this time but our supporters deserved a good and competitive quality passing performance, that was the team talk and that is what we got.
"We have beaten the best team in the league and we were unlucky not to score more goals."