Stand-in striker Danny Mitchley hit the only goal of the game as Mansfield Town took the first-leg honours in Sunday's FA Trophy semi-final at Field Mill.
Mitchley, only playing because of a back injury to Louis Moult, struck on 62 minutes with a low shot.
Luton keeper Kevin Pilkington got a hand to it but could not prevent it going in off an upright.
The Hatters had their chances but were denied by an inspired goalkeeping display from Mansfield's David Grof.
Stags captain Adam Murray was ineligible as part of the agreement that saw him move from Luton earlier in the season.
Weakened Luton, who suffered only their second defeat in four months, were minus a clutch of players.
As well as long-term absentees Adam Newton (calf), Charlie Henry (ankle), Shane Blackett (groin) and Alex Lacey (bruised bone), they were without the cup-tied Robbie Willmott and Paul Carden.
Luton's assistant manager Gary Brabin told BBC Three Counties Radio: "We were a little disappointed in the performance as I think we're a lot better than that.
"If it had been nil-nil I think we'd have been a lot happier, but we know what we've got to do on Saturday.
"We'll get the crowd behind us and make sure it makes for a good semi-final."
The second leg is next Saturday (19 March, 1500 GMT) at Kenilworth Road.
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