Giorgio Rasulo struck the only goal of the game after 34 minutes.
Tom Carroll, Jake Livermore and Andros Townsend all played 73 minutes after returning from the Barclays Asia Trophy in Hong Kong.
There were plenty of chances as MK edged the first half and then held firm as we piled on the pressure in the second half.
Jonathan Miles and Ian McLoughlin made comfortable saves inside the opening 15 minutes, Livermore headed just wide from Carroll's corner and Patrick Bamford steered a one-on-one wide.
Cameron Lancaster blasted just over from the edge of the box midway through the half and the home side should really have taken the lead on the half-hour when Zavon Hines zipped in a cross from the left only for Will Summerfield to miss the target from close range.
Yago Falque fired across goal from a tight angle on 33 minutes and the home side opened the scoring a minute later. Rasulo burst through centrally, Miles saved the initial one-on-one but could do nothing to stop Rasulo tucking away the rebound.
Miles then denied Bamford twice, the first a flying save to his right to palm away a 25-yard free-kick, the second sharply off his line to block one-on-one.
Jordan Archer replaced Miles and Coulthirst came on for Lancaster for the second half.
The second half started somewhat scrappily but warmed-up on the hour when Cristian Ceballos sent Coulthirst clean through. The striker measured his finish past McLoughlin, but the ball ran just the wrong side of the post.
MK responded with a quick break that led to Archer making a fantastic close-range block from Kelvin Osei-Addo and seconds later, Ben Reeves shaped as if to cross a free-kick from the right but ended up whipping the ball on target a clipping the top of the crossbar.
We made three substitutions on 73 minutes with Kenny McEvoy, Giancarlo Gallifuoco and Ruben Lameiras replacing Townsend, Livermore and Carroll.
McEvoy looked lively down the left and went close on 78 minutes when he cut in and let fly with his right foot. Coulthirst tried to turn the ball on target but ended up diverting it wide.
The Irish winger was involved again three minutes from time when he latched onto Ceballos' pass on the right. This time he drilled across McLaughlin but just wide.
The final chance arrived in the final minute as Falque took aim from 20 yards but substitute goalkeeper Charlie Burns followed McLoughlin's lead and palmed away to his left.
MK Dons McLaughlin (Burns, 88); Baldock, Otsemobor (Weston, 76), Flanagan, Galloway (Osae, 58); Hines (Grant, 72), Reeves (Tingey, 76), Alli (Wiltshire, 58), Summerfield; Rasulo, Bamford (Osei-Addo, 58).
Spurs (4-3-3): Miles (Archer, 46); Fredericks, Livermore (Lameiras, 73), Stewart, Ward; Bentaleb, Carroll (Gallifuoco, 73), Falque; Townsend (McEvoy, 73), Lancaster (Coulthirst, 46), Ceballos.
Goals: MK Dons - Rasulo (34).
Referee: Mr K Stroud.