Big centre-forward Clive Platt, making his Dons debut after signing from Peterborough in midweek, proved the ideal foil for the diminutive Wade Small as the pair tore the U's apart.
Small grabbed a superb goal and set up another for Ben Harding, while his 6ft 4in strike partner helped himself to an assist and saw his fierce drive rattle the bar.
The Dons got off to a flying start, with Harding taking only two minutes to score on his long awaited return to the side after a cruciate ligament injury.
Small got clear and acrobatically lobbed Dean Gerken in the Colchester goal, but as Sam Stockley looked set to clear he mistimed his header, leaving Harding with the simplest of finishes into an open goal.
Platt looked set to double the lead when he burst through in the seventh minute and fired a ferocious half-volley onto the bar.
But the lively Small duly grabbed Milton Keynes' second in the 18th minute, racing onto Platt's headed flick and finishing clinically past Gerken as the U's defence appealed for offside.
At the other end, Colchester should have pulled a goal back just two minutes later when Gareth Williams blazed over an open goal from eight yards after an error by Dons keeper David Martin.
But normal service was resumed after the break and Gary Smith was unlucky not extend the home side's lead further when his thunderous 25-yard volley rattled the bar just seconds after the re-start.