Rory McAuley grabbed the only goal as Cambridge made it three wins on the spin at Luton's expense.
The home side had the best of the first half, Danny Crow's header testing Danny Naisbitt and Stuart Fleetwood firing over.
But Cambridge bossed the second half, Luke Berry twice going close before Josh Coulson crossed for McAuley to nod in the winner.
Jez George's men are now eight unbeaten and just outside the play-offs.
VIEW FROM THE DRESSING ROOM
Luton Town manager Gary Brabin told BBC Three Counties Radio:
"I'm obviously disappointed, frustrated, angry.
"But it is early days, obviously we're disappointed but you look around at other results and the top sides seem to be finding it hard to get momentum.
"First half I thought we came out the traps quite well, played with a tempo, and second half they've got bodies behind the ball, tried to frustrate us and scored against the run of play."
Cambridge manager Jez George told BBC Radio Cambridgeshire:
"I can say all the cliches I like before the game about it just being three points, but I know there's an edge to this game.
"You only have to look at the number of former players here and the location, in terms of how close it is to Cambridge.
"We want our fans to be proud of their team and make sure they go home happy after they've seen us play, so I'm delighted with the result."