Goals from Matt Jay, Joel Randall and a hat-trick from Ryan Bowman earn the Grecians all three points, as Michael Folivi nets a consolation for Steve Ball's side on the road at Exeter.
Steve Ball named an unchanged line up from their last game, a 1-1 draw away at Mansfield on Friday night, including an unchanged bench.
The home side were looking for a fast start against the U's after their defeat at the weekend to Oldham and went close a couple of time in the opening ten minutes.
Archie Collins was first to have a shot on goal and he just dragged his effort wide of Gerken's far post, but Joel Randall missed a sitter with seven minutes played. He latched on to a cross at the back post from Jay before lifting the ball over Gerken's unguarded goal from little more than a yard out, while being pressured by Miles Welch-Hayes.
And it was the home side that found the first breakthrough in the game after twenty minutes had been played at St James Park. Matt Jay was the man to get on the score sheet as he latched on to a cross at the near post and cleverly knocked the ball beyond Gerken to give his side the lead.
Exeter looked the better side for the first period, dangerous when they were attacking down the wings, with Steve Ball opting to change shape, switching to a 3-4-3 formation.
But the Grecians kept coming and nearly added a second just before half time. Matt Jay broke away down the right wing, before firing his effort just wide of Gerken's goal.
Trailing at the break, U's boss Steve Ball made further changes at the break, this time switching personnel. A triple substitution saw Poku, Welch-Hayes and Chilvers replaced by Norris, Folivi and Harriott.
The home side doubled their lead eight minutes after the break though, as Jay turned provider to Joel Randall. Jay ran through and made Gerken commit before sliding the ball through to Randall who had an empty net to tap in to.
Three minutes later it was a three goal advantage to the Grecians as Bowman added a third from close range. He got on the end of Sparkes' cross to smash the ball home from inside the six yard area.
Ryan Bowman added another with just less than twenty minutes to play, as he was free in the area and able to finish easliy from Joel Randall's low cross.
But two minutes later the U's had a goal, and it was Michael Folivi's first league goal for the U's. A brilliant lofted ball from Harriott picked out the U's substitute, who took the ball towards goal before jinking inside and sliding his effort in off the post.
Exeter front man Ryan Bowman completed his hat-trick in added time after Gerken saved initially from Sparkes' shot before Smith cleared the ball against Bowman with the ball bouncing in.
Matt Taylor's side added a sixth with Matt Jay who reacted quickest to tap in Bowman's effort that struck the post moments before the full time whistle blew.
Colchester United return home in their next game, as they take on Crawley at the JobServe Community Stadium on the 1st December.
Exeter City starting XI: Andresson, Sparkes, Taylor, Collins (Atanga 81'), Williams (Ajose 82'), Bowman, Randall (Hartridge 76'), Parkes, Jay, Sweeney, Key.
Unuseds subs: Lee, McArdle, Law, Fisher.
Colchester United starting XI: Gerken, Welch-Hayes (Norris 46'), Bramall, Smith, Senior (Poku 56'), Pell, Brown (Bohui 74'), Chilvers (Folivi 46'), Eastman, Poku (Harriott 46'), Stevenson.
Unused subs: George, Sowunmi.