Two Gary Madine goals in ten second half minutes and a late Liam Palmer strike saw Wednesday maintain their 100 per cent S6 start to the new campaign.
The in-form Madine proved the difference as the striker's tally for the term went to five and the Owls rose to eighth in the League 1 table.
Angelo Balanta was on the scoresheet for MK, but it was not enough to prevent their first defeat of the campaign.
With Jermaine Johnson returning from a knee injury, Wednesday could utilise the winger's trademark pace and trickery, both of which were in evidence in the early exchanges.
On the other flank, Ben Marshall looked lively and his first cross of the contest saw the onrushing Clinton Morrison a whisker away from close range contact.
For their part, MK Dons played some nice football without creating anything tangible as the opening period unfolded.
The same could be said of the Owls, though, who forced a string of corners towards the break but failed to really trouble the Dons' defence.
MK goalkeeper David Martin was called into action moments before half time when he had to stretch to divert Julian Bennett's looped effort over the bar and Lewis Buxton went close from the resulting corner.
But by and large, Martin and counterpart Richard O'Donnell were spectators through an uneventful first half.
Johnson failed to appear for the second 45 and Palmer came on his place.
The visitors came out with more purpose - O'Donnell dived low to keep out a low drive from Jabo Ibehre - but Wednesday promptly stemmed the danger by taking the lead on 54 minutes.
Morrison did well in the area to turn and find Madine, who slotted home past the despairing Martin.
And ten minutes later, Madine made it two. Palmer drilled a vicious cross right into the mix and Madine climbed high to power an unstoppable header into the back of the net.
Wednesday continued to dominate, with MK offering little in attack - until substitute Balanta jinked his way through the Owls' backline on 77 minutes to hand the visitors a lifeline.
And two minutes later, they came close to completing a comeback but O'Donnell came to the Owls' rescue with a wonderful flying save from a crisp Dean Bowditch drive.
And that proved a key moment in the game, which was duly underlined when Palmer side-footed in Madine's feed on 89 minutes to finally put the points out of reach.
To round off a miserable afternoon for MK, Ibehre saw red in the final minute for a second bookable offence.
Owls: O'Donnell, Buxton, Bennett, Batth, Jones, Semedo, Prutton, Marshall (Lines 90), J Johnson (Palmer 46), Madine, Morrison (O'Connor 83)
Unused substitutes: Jameson, R Johnson
MK Dons: Martin, Smith, Lewington, MacKenzie, Williams, Chadwick (MacNamee 87), Gleeson (Balanta 26), Potter, Bowditch, Ibehre, MacDonald (Powell 71)
Unused substitutes: McLaughlin, Chicksen