The Hatters needed to win the match at Pride Park to have any chance of staying up, but were sunk by Lewin Nyatanga's close-range strike just before the break.
It was the only goal of the game, and condemmed Luton to relegation.
With the season heading into the final games, Leeds and Southend occupy the final two relegation spots in that division - though both will live to fight another day regardless of results this weekend.
In League One, Bristol City could seal promotion with a win at in-form Carlisle United - but only if Nottingham Forest slip-up at home to Bournemouth.
If City fail to win it would hand Scunthorpe the title, which they would all but claim if they picked up all three points at Tranmere as they would then be six points clear with just two games to go.
Chesterfield could be relegated to League Two if they lose to Northampton, but only if Cheltenham and Leyton Orient both pick up wins.
Hartlepool and Walsall have already been promoted to League One, with Swindon able to join them in making the step up if they better MK Dons.