Luton produced a powerful finish to claim all three points at Prenton Park.
The Merseysiders had been gifted a first half lead but were often at sixes and sevens in a below par performance.
Gareth Roberts, their best player on the day netted the opener in the 22nd minute with a close range shot. The ball fell to him after Luton keeper Cedric Berthelin had firstly kept out a Stuart Barlow penalty and then a follow up shot by Marvin Robinson.
Skipper Kevin Nicholls conceded the penalty when he handled a throw-in by Roberts.
But Luton always looked dangerous and they made up for not scoring in their previous three league matches with three goals in the last 21 minutes.
Matthew Spring netted with an angled shot in the 70th minute after a mis-hit effort by Steve Howard.
Then Tony Thorpe provided the cross for Ahmet Brkovic to produce a stylish finish from 12 yards.
Howard wrapped it up in the 89th minute, netting at the second attempt after his first shot had rebounded off keeper John Achterberg.
"The first goal took a long time coming but it was inevitable and Tranmere collapsed afterwards," said Howard.
Luton boss Joe Kinnear said: "We were much braver in the second half and created numerous chances but once we got the first goal I never had any doubt over the result.â€ Tranmere manager Ray Matthias was seething: "We never won enough ball and gave them far too much space. They caused us a lot of problems and it is back to hard work on the training ground next week.â€