Both sides created plenty of chances and struck the woodwork, but a Scott Fraser penalty late in the first half proved to be the only goal.
And there was further bad news for the Blues, with Jack Whatmough set for a lengthy suspension after being sent off for a late lunge.
Danny Cowley made one enforced change from the side that played out a goalless draw at Crewe earlier in the week.
Ben Close missed out with a groin injury, so Tottenham loanee Harvey White came in for his first start in just over a month.
Andy Cannon – struggling with a back problem – was only fit enough for a place on the bench, where he was joined by former Dons defender Paul Downing.
A minute’s silence was held before kick-off in memory of His Royal Highness The Prince Philip, Duke of Edinburgh on the day of his funeral.
The game began at a fair old pace and never really relented, with both sides looking to get forward whenever possible.
It was the hosts who dominated possession in the first half, although Pompey looked particularly dangerous in the break.
Ronan Curtis was first to threaten with a shot from the edge of the box that flew straight into the arms of Andrew Fisher.
Their opponents went closer soon after, as a Matt O’Riley curler rattled the woodwork and Andrew Surman’s follow-up narrowly cleared the crossbar.
O’Riley then should have done better, glancing a close-range header wide after being picked out in the box by Fraser.
The action continued to switch from one end to the other and an acrobatic over-head kick from John Marquis was brilliantly kept out by Fisher.
And when the keeper was spotted off his line, Marquis attempted an audacious strike from the halfway line that flew not too far off target.
It seemed to be a question of when, rather than if, a goal would be scored and Ethan Laird flashed a dangerous low delivery across the Blues box that none of his team-mates could get on the end of.
Curtis then had a couple of attempts in quick succession, firing one just past the post and seeing a second gathered at the second attempt by Fisher.
But it was the home side who finally broke the deadlock on 41 minutes after Charlie Daniels was punished for a trip on Laird.
Replays showed the challenge took place just inside the box and Fraser sent Craig MacGillivray the wrong way from the spot.
That was not the end of the first half action, though, with both sides unfortunate not to score in stoppage-time.
Will Grigg’s effort was brilliantly blocked on the line by Sean Raggett, while Daniels was the man stationed there to keep out his follow-up.
Pompey immediately made their way up the other end and Curtis cut the ball back for Marquis, whose attempt was deflected over.
MK Dons 1
The action did not let up following the interval and when Grigg laid off O’Riley’s cross, Fraser’s shot rattled the crossbar.
Tom Naylor then sent a dangerous low cross to the back post, but Curtis could not quite arrive in time to poke it home.
And the resulting corner from Daniels was met by Naylor, whose header hit the bar, bounced down onto the line and was cleared.
Cowley made a double switch just before the hour mark, as Ryan Williams and White made way for Rasmus Nicolaisen and George Byers.
It saw a switch to playing three at the back, as the Blues looked to find a different route past their opponents.
The chances had started to dry up, with MK Dons seeming more than happy to protect their narrow lead.
A Daniels free-kick was nodded back by Whatmough on 70 minutes and Fisher failed to keep hold of the ball, although fortunately for the keeper it landed at the feet of one of his team-mates.
Raggett was replaced by Andy Cannon for the closing stages, as the Blues kept plugging away in search of a leveller.
But their hopes were dealt a blow when Whatmough was shown a straight red card – his second of the season.
The defender took a heavy touch and dived in two-footed on Charlie Brown to try to win the ball back.
There was not too much connection made with the Dons substitute, but referee Martin Coy deemed it dangerous enough to send the centre-back off.
And although there was still plenty of endeavour being shown by Pompey, their opponents saw the game out to claim the points.
MK Dons (3-5-1-1): Fisher; Lewington (c), Darling, Jules; Laird, O’Riley, Surman (Houghton 84), Kasumu (Brown 66), Sorinola; Fraser (McEachran 66); Grigg
Goals: Fraser 41 (pen)
Booked: Lewington, Jules
Subs not used: Nicholls, Sørensen, Bird, Mason
Pompey (4-2-3-1): MacGillivray; Johnson, Whatmough, Raggett (Cannon 76), Daniels; Naylor (c), White (Byers 58); Harness, Williams (Nicolaisen 58), Curtis; Marquis
Sent off: Whatmough
Booked: Daniels, Byers
Subs not used: Ward, Bolton, Downing, Stanley
Referee: Martin Coy