Substitute Sam Baldock scored twice for the Dons as they piled more misery on struggling Colchester.
Mark Wright found an unmarked Aaron Wilbraham, who fired the opener past goalkeeper Dean Gerken.
Colchester's Mark Yeates' hit the post with a free-kick before Baldock shrugged off Paul Reid to collect Dean Lewington's long pass and score.
And Baldock tapped in a third in stoppage-time from Wilbraham's low cross to seal victory for the Dons.
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Milton Keynes Dons: Gueret, Regan, Llera, O'Hanlon, Lewington, Wright, Navarro, Leven, Cummings, Gerba (Baldock 72), Wilbraham. Subs Not Used: Abbey, Stirling, Johnson, Belson.
Booked: Wilbraham.
Goals: Wilbraham 2, Baldock 88, 90.
Att: 4,888
Ref: Trevor Kettle (Rutland).
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