It was a game that swung both ways as both sides led at different stages of the game, but the visitors came out on top as goals from Robbie Simpson, Ollie Watkins and Joel Grant were enough secure three points for Paul Tisdale's men.
Exeter City came out on top in a five goal thriller as Colchester suffered only their second league defeat of the campaign on Saturday afternoon.
Colchester had come from behind with Sammie Szmodics scoring in successive league game and Kurtis Guthrie had given the U's the lead but, in the end, it proved a frustrating day for the U's.
The U's started the first half in uncharacteristically slow fashion and gifted several openings for the visitors.
And one cost the U's the first goal as Exeter took the lead through a set piece.
Jordan Moore-Taylor climbed highest to meet a cross but his header rebounded off the base of the post, only for Robbie Simpson to react quickest and tap home the rebound from close range.
One should have been two moments later as a misplaced pass from Tom Eastman should have been punished.
Jack Stacey was slipped through on the edge of the box and he looked to have set up Simpson for his second goal of the game but he somehow managed to smash the ball over the bar from close range.
And Exeter were made to rue this missed chance not long after as Colchester equalised against the run of play.
Another set piece but this time for the U's, led to Ryan Harley attempted clearance with his head go straight to Szmodics.
He was able to control the ball on his chest and emphatically drill the ball low into the net to level the scores at 1-1.
In an end to end game, both side looked dangerous on the counter attack and it was Exeter who could have retaken the lead. Jake Taylor found himself in space on the edge of the
box, but his low shot was well saved by Sam Walker and the ball was cleared to safety.
Another let off for Colchester and another costly miss by Exeter.
Especially after a quiet spell in terms of chances for both sides was abruptly ended by Kurtis Guthrie in the 38th minute. Brennan Dickenson delivered a dangerous cross and Guthrie managed to loop a header over Bobby Olejnik in the Exeter goal to make it 2-1.
This goal put an end to the goalmouth action in the first half as both sides failed to create any more opportunities and Colchester led 2-1 at the break.
The second half was as entertaining as the first half but ultimately a disappointing one for the U's and the home crowd.
The fourth goal was always going to be crucial and it was Exeter who grabbed it not long after Szmodics had another good chance go wide.
In the 51st minute, Watkins received the ball on the edge of the box and drilled the ball past the diving Walker. It was Watkins' quick feet and cut inside that allowed him to get his shot away and it left Walker with no chance.
The equaliser for Exeter led to new loan signing, Tarique Fosu's introduction and the youngster was straight into the action.
He was straight into the action as he picked up the ball in the box but his cross somehow evaded everyone, much to the annoyance of U's players and fans alike.
Just like Exeter's second goal, this missed opportunity proved very costly as Exeter took the lead with the next attack. Substitute Grant was provided with a tap in at the far post as he got on the end of a great cross by Jack Stacey.
The visitors sat back after retaking the lead and prepared for the Colchester onslaught.
Fosu was proving a real danger and he forced Bobby Olejnik into a smart stop to tip over a powerful shot. Olejnik was forced into action again with just 10 minutes left as tipped over a powerful header from Prosser.
Fosu had another great chance to level things but his shot was blocked superbly as a goal looked certain.
Then came a real controversial moment as with just two minutes of normal time to go, Colchester sub Denny Johnstone was judged to be offside as he bundled the ball home from close range.
There was more chaos deep into injury time as Colchester were desperately trying to find an equaliser.
The ball broke kindly for Szmodics in the box but his shot from 4 yards out cannoned off the woodwork and out for a goal kick.
In the final few moments Colchester had several corners and Walker was sent forward in an attempt to nick a goal but, after a scramble, Exeter managed to clear the ball and the final whistle was blown.
A disappointing day for the U's and a reminder of how tough League Two can be, but they have the chance to put thing right next week when Blackpool travel to the Weston Homes Community Stadium.