Chairboys defender Ryan Tafazolli opened the scoring from a corner in the 37th minute, while Sam Vokes doubled the hosts’ advantage eight minutes from time at Adams Park.
Vokes’ headed goal came after MK Dons midfielder Josh McEachran received a second yellow card for a late challenge on Josh Scowen midway through the second half.
McEachran will now be suspended for Sunday’s second leg at Stadium MK, which will take place at the earlier time of 6:30pm.
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Away goals do not count in the play-offs and semi-final ties will go to extra time and penalties if the aggregate score is level.
The Black Cats will then travel to Hillsborough for the second leg on Monday.