The visitors had taken the lead and, after Jabo Ibehre missed a penalty to draw the U's level, he made amends with a fantastic run and finish early in the second half.
After a six week absence, the U's returned to home action on Saturday, but were edged out by a late Preston winner in a close encounter at the Weston Homes Community Stadium.
But it was the visitors who grabbed it with a late winner, which had more than a hint of offside in the build up before Brian Wilson turned into his own net.
The promotion chasing Lilywhites came to town with the second best away record in the league and pressured Colchester from the first minute.
Preston top scorer Joe Garner had the first big chance of the game when he rose to meet Craig Davies cross, but his header was inches too high and bounced clean off the front of the cross bar.
The away side continued to create more chances with Garner again coming close after his deflected shot wrong footed Sam Walker and whistled just wide of the post.
At the other end U’s had their own chances with two free kicks just outside of the box but had no success testing Declan Rudd in the Preston goal.
Dom Vose impressed with some impressive runs out wide and in through the middle of pitch but didn’t have the support to create any significant chances for the U’s.
Bang on the half hour mark Preston took the lead through Clarke, the defender latched onto Paul Gallagher’s corner to head in the opening goal via the underside of the crossbar.
As Colchester looked for an instant response just minutes later referee Gillett awarded them a penalty when Declan Rudd appeared to let loose Jabo Ibehre’s shot and then bring down Marcus Bean as he chased the ball.
Ibehre stepped up to talk the penalty but couldn’t convert with Rudd who escaped a red card, diving low to his right and holding the ball.
Preston saw out the remainder of the half with their lead still intact at a ground in which they’d never achieved a league victory.
U’s looked to continue their fight back after the break and within ten minutes Ibehre made up for his penalty miss with a fantastic solo equalising goal.
This came is he darted past Clarke and into the box looking to pick out Craig Eastmond, the pass deflected back and Ibehre had enough time to open his body and curl a shot into the top corner.
Colchester pushed on with the momentum swinging in their favour but struggled to find the killer pass. Ibehre had the best of the chances but his deflected shot bobbled just wide of the post.
The prolific goal scoring Garner had the perfect chance to put Preston back ahead but Sam Walker was there to respond with a fantastic save.
This lead to a lightning counter attack which put Jabo Ibehre through with a ball to chase but Rudd was perfectly timed to come out and sweep the ball away.
Substitute Freddie Sears nearly made an instant impact as he raced past defenders and crossed to Ibehre but the strikers touch was heavy and the chance fizzled out.
But Colchester’s chances to take the lead looked all the more important as Preston took a fortuitous lead through a Brian Wilson own goal.
Chris Humphrey collected the ball from Garner who had looked to be in an offside position before racing into the box, his low drive across goal hit the rushing Wilson sending the ball over the line.
With just minutes to go Jack King raced through on goal with a chance to finish the game but Ryan Dickson made a perfect sliding challenge to dispossess King and clear the ball.
The fresh legs of Clinton Morrison and Freddie Sears lifted Colchester in the final third but there was no final result for Joe Dunne’s side.
Having thrown everything at it Colchester were made to pay for Ibehre’s vital penalty miss and couldn’t find an second equalising goal, giving Preston their first win in Colchester since 1986.