First-half strikes from Izale McLeod and Clive Platt plus Tommy Lee's late own goal condemned Paul Ince's Silkmen to their fifth straight away defeat.
McLeod gave the Dons a dream start when he bundled his way past Macclesfield defenders Dave Morley and Carl Regan to flick his 22nd goal of the season over goalkeeper Lee from five yards in only the second minute.
The lively McLeod thought he'd won a penalty three minutes later when he intercepted Danny Swailes' weak backpass and was sent flying by Lee's diving challenge in the box, but the Silkmen keeper did well to get a hand on the ball.
The Dons continued to dominate the first half with some neat passing football and Platt headed Jon-Paul McGovern's cross wide before volleying Gareth Edds' inviting centre wide from ten yards.
Macclesfield took 41 minutes to register their first shot on target, but Swailes' fierce 30-yard free-kick was straight down Dons keeper Lee Harper's throat.
Platt deservedly put Milton Keynes 2-0 up on the stroke of half-time when he rose above Swailes to head McGovern's in-swinging free-kick into the top corner from seven yards for his 14th goal of the season.
McLeod stung keeper Lee's hands with a rasping left-foot drive from 12 yards after skinning hapless centre-half Swailes down the right seven minutes after the break.
And McLeod should have made it 3-0 when he beat Swailes and Macclesfield skipper Morley but then blazed the ball over from nine yards.
At the other end, Silkmen substitute Matty McNeil nipped in ahead of Dons keeper Harper to a routine long ball, but his cross from an acute angle was too far behind strike partner John Murphy with the goal gaping.
Milton Keynes continued to press and McLeod was denied by a brave block from Lee one-on-one, before the Macclesfield keeper's unlucky own goal made it 3-0 in the 77th minute.
McGovern's drilled 22-yard drive from Platt's lay-off came back off the post, but the ball bounced off the floored Lee's back and trickled into the net.