Colchester had taken a 43rd minute lead from Clive Platt, but Charlie Daniels levelled on the stroke of half-time before McGleish scrambled home the winner from point-blank range.
It was the perfect result for Orient boss Geraint Williams, who parted company with the U's earlier in the season.
But, in an uninspiring first half, it was Colchester who dominated for long spells.
However, it was Orient who created the first chance when Jimmy Smith's ball into the danger area fell to Simon Church who rolled the chance wide.
After that the visitors took a vice-like grip and the impressive Simon Hackney tested Orient keeper Jamie Jones.
Then Paul Terry cleared Platt's header off the line as Colchester threatened and the visitors' striker went close again when he touched a Hackney free-kick just wide.
But Platt was not to be denied and he broke the deadlock on 43 minutes with a close-range header after Lewis Gobern had flicked the ball on.
Orient's response was immediate and Daniels blasted home a free-kick from 30 yards during stoppage time.
After the interval McGleish had a shot pushed away by Colchester keeper Dean Gerken and the visiting keeper then made a wonder save from JJ Melligan.
Orient looked a much better side after the break and McGleish wasted a good chance to put the home side ahead before both sides hit the woodwork.
Marc Tierney smacked an effort against Orient's bar from distance then McGleish did likewise at the other end.
But it was Orient who won the game ten minutes from time when Smith lobbed the ball over keeper Gerken and McGleish slid the ball home from close to the line.