Goals from John Melligan and Adrian Patulea did the damage for Leyton Orient as memories of Colchester's 7-1 opening day win against Norwich were extinguished.
To make matters worse for Colchester, striker Clive Platt was needlessly sent-off late on in the game for an incident in the penalty area and will now serve an untimely suspension.
Winger Melligan got the better of Lee Beevers inside two minutes to set up the first goal for Patulea to head home past Mark Cousins.
Jimmy Smith could have doubled Leyton Orient's lead not long after but this time Cousins was on hand to make a timely save for the home side.
Andros Townsend also went close for the visitors as Colchester were in danger of being embarrassed by Leyton Orient.
Simon Hackney and Kevin Lisbie both had good chances to level for Colchester but the latter fired wide, while Glenn Morris produced a superb save from Lisbie.
Lisbie wasted two further chances with his head, with Morris delighted to see both fly wide of the uprights.
Smith was then left frustrated for Leyton Orient as he saw his effort cleared off the line just seconds before the half-time whistle.
On 63 minutes Leyton Orient appeared to put the game to bed as Melligan scored from a narrow angle but just minutes earlier Platt felt as though he'd been denied a goalscoring opportunity.
Colchester wasted an avalanche of late opportunities to haul themselves back into contention.
And finally with what proved to be the last kick of the game Hackney drilled the ball home but it proved too little too late for Colchester.