Despite playing an entire half with an extra man, Orient were unable to breach the Colchester defence and the visitors made them pay by capitalising on some slack defending to secure a 2-0 victory at the Matchroom Stadium.
There was very little goalmouth action in an otherwise frantic first half which saw three U's players booked and their captain, Magnus Okuonghae, sent off for a bad challenge on David Mooney.
As is often the case when teams are reduced to 10 men, Colchester rallied in the second-half and had the quality and pace required to punish the O's on the counter-attack.
First, Sanchez Watt raced through on goal to fire them into a 62nd minute lead before Freddie Sears dispossesed Mathieu Baudry nine minutes later and finished emphatically past O's keeper Gary Woods, who had denied the striker on several previous occasions.
It was Orient's first defeat since the opening day of the campaign but leaves them still searching for their first home win of the season.
The international break afforded Russell Slade some valuable time on the training pitch with his side after a hectic month which involved thousands of miles of travel.
The break also saw Orient sign 19-year-old QPR winger Michael Petrasso on a one-month loan and Slade named the youngster in his line-up for today's game.
The O's boss made two further changes to the team that started in the Johnstone's Paint Trophy win over Peterborough a week-and-a-half ago, with Marvin Bartley and Darius Henderson replacing Lloyd James and Romain Vincelot who were not available due to injury and suspension, respectively.
It wasn't the strongest starting 11 that Slade is able to name, with a number of players - including goalkeeper Adam Legzdins who has a damaged finger and Kevin Lisbie - also out injured, however the home side were able to call upon a strong bench containing the likes of Dean Cox and Jobi McAnuff who were not quite fit enough to start but ready to be introduced if required.
Unlike Orient, Colchester played last weekend - a goalless draw with Walsall - and recently-appointed manager Tony Humes named an unchanged side for this fixture.
New signing Petrasso was lively on the ball in the opening exchanges, drawing a number of free-kicks as the U's defence struggled to come to terms with his energy, and the Canadian also found himself on free-kick and corner-taking duty in the absence of James.
However it was 20 minutes before either side had an attempt on goal, when David Mooney's low delivery found Henderson at the near post but the striker couldn't quite adjust his body shape in time to get his effort on target.
Orient were completely dominant in possession throughout the half and continued to be fouled persisitently by their opponent's, with referee Keith Stroud forced to book two players inside the opening half an hour.
And Baudry thought he had been impeded inside the U's box 10 minutes before half-time when he poked the ball past Colchester's Sam Walker but the goalkeeper was seen to get a hand to the ball before Baudry was felled. Chris Dagnall was first to the rebound after that particular incident however brave defending from the away side saw his close-range effort deflected over the bar.
Moments later Dagnall sent another effort narrowly over when he met Scott Cuthbert's teasing cross which came at the end of a brilliant passing spell from the home side.
Failing to take on board the referee's countless warnings over the strength of their tackles throughout the first half, Colchester were reduced to 10 men when Magnus Okuonghae flew into a challenge with Mooney on the left side of the pitch a minute before the break - the U's captain had not been booked previously but was shown a straight red for his lunge.
Orient piled on the pressure for the remaining moments of the half and another good delivery from Cuthbert was almost dispatched by Henderson at the far post before Stroud signalled for the break.
The O's came flying out of the traps in the second half, under clear instructions from Slade to go after an early goal, and full-back Shane Lowry fired a speculative volley wide of the left post after Petrasso had forced a corner in the opening minute.
But it was Colchetser who were presented with the most clear-cut chance of the game minutes later when a through ball bounced over the head of Baudry and was met by Sears who had snuck in behind but, luckily for the O's, goalkeeper Gary Woods was alert enough to make a superb save from Sears' lobbed effort.
With the visitors down to 10 men and Orient pushing men forward early on, the game was a much more open affair in the second half.
And after a period of decent pressure from the O's, during which they won a series of corners, Colchester launched a devastating counter-attack which saw Sears send fellow forward Watt through on goal and the former Arsenal youngster raced away from Marvin Bartley before slotting home past Woods.
Orient continued to force corners and came inches away from equalising as a result of one on 65 minutes when Lowry sent a powerful header goalwards only for Walker to make stunning one-handed save low to his left.
Slade responded to going behind by introducing Cox and McAnuff but Colchester could have found themselves further ahead when a mistake from Baudry allowed Sears in again, but the striker was denied once more by Woods.
And moments later, the visitors did double their lead when Baudry tried to shepherd the ball out of play after a long ball forward, only for Sears to pinch it off the O's defender before closing in on goal and this time firing past Woods into the net.
The O's did not give up on the cause and continued pressing forward, but when Henderson and substitute Jay Simpson were both presented with glorious opportunities late on, neither could apply the required finish.
Chris Dagnall also found himself in a great position midway through the five minutes of time added on, but a heavy touch allowed Walker to get to the ball before he had chance to get his shot away.
A wild volley from Henderson was the last action of a game where Orient will rue not capitalising on their one-man advantage and giving Colchester the opportunity to punish them on the counter-attack.
ORIENT:Woods; Cuthbert (Simpson, 82), Baudry, Clarke (C), Lowry; Petrasso (McAnuff, 69), Bartley (Cox, 65), Pritchard, Mooney; Dagnall, Henderson
SUBS: Grainger, Omozusi, Lee, Batt
BOOKINGS: Lowry (37), Pritchard (87)
COLCHESTER: Walker, Gordon, Okuonghae (C), Watt (Eastmond, 74), Gilbey, Sears, Eastman, Clohessy, Massey, Moncur (Vose, 80), Szmodics (Kent, 45+1)
SUBS: Lewington, Wright, Eastmond, Lawrence, Bonne
GOALS: Watt (62), Sears (73)
BOOKINGS: Moncur (21), Gordon (26), Gilbey (44), Watt (68)
RED CARDS: Okuonghae (44)
REFEREE: Keith Stroud
ATT: 5,313 (711)