Two excellent first-half strikes from on-loan Luke Chadwick saw MK Dons take the points.
But they had to battle after the break when Shaun Cummings was sent off, but despite Tamika Mkandawire's 90th minute strike, Leyton Orient have now gone nine games without a win.
The visitors had too much pace and power for Orient in the first half and almost took the lead on six minutes, when skipper Dean Lewington raced down the left and crossed for fellow full-back Jude Stirling to crash the ball against the post.
But it did not take long for MK Dons to make the all important breakthrough.
The opening goal arrived on 19 minutes when Chadwick, on loan from Norwich, played a neat one-two with Peter Leven and finished from six yards.
Four minutes later it was 2-0 and Chadwick again provided the finish with a cheeky back-heel inside the six-yard box following Mark Wright's right-wing cross.
Orient were stunned as they could not cope with the visitors' pace and power down the flanks.
Orient boss Martin Ling made a double change at half-time as Sean Thornton and John Melligan replaced Paul Terry and Dean Morgan and the home side suddenly sprung into life.
Adam Chambers forced Dons keeper Lewis Price into his first save on 47 minutes and 60 seconds later Cummings saw red when he tripped Thornton as he raced clear.
Referee Clive Penton pointed to the spot, but Orient top-scorer Adam Boyd put his spot-kick well wide.
But Orient took control against the ten men visitors as substitute Thornton was the driving force.
Thornton shot wide and Melligan was denied by Price as the home side continued to control the game.
Home skipper Stephen Purches saw an effort saved before substitute Ryan Jarvis twice went close in stoppage time.
Orient were finally rewarded in the fourth minute of injury time when Mkandawire smashed home from close range following Thornton's cross, but it was too little, too late.