Veteran striker Kevin Gallen notched the winner to send MK Dons up to fourth in the League One table.
Tranmere's Charlie Barnett had the first decent attempt with a shot from 18 yards but Antony Kay and Ben Chorley had to be alert to keep MK Dons at bay.
The home team started the second period well as Jason Puncheon and Luke Chadwick had powerful shots blocked.
But late substitute Gallen broke the deadlock after he scored almost instantaneously from Puncheon's corner.
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