It started well, with Rhys Healey putting them ahead, before Preston scored twice in five minutes.
Alex Gilbey got the score back to 2-2 on thirty six minutes, ending the scoring in an exciting first half.
It only took Preston a minute to regain the lead at the start of the second period, before they made the game safe at 4-2 just before the hour mark.
The defeat put the U's back in the relegation zone, but they had given one of the favourites for promotion a real run for their money.
After his goalscoring debut from the bench, loanee Rhys Healey came into the starting line-up against Preston, replacing Craig Eastmond.
It was Eastmond that Healey replaced at Crewe, coming on alongside Sears and Watt in a front three.
That was the plan at Deepdale, with Massey dropping into the hole, a position he filled so well seven days ago in Cheshire.
It was the hosts who started the game on the front foot, with it taking them only two minutes to get the first effort away.
And it really should have put them on the scoresheet, but Gallagher rolled his left foot shot wide after being put in by Garner.
It didn’t unsettle the U’s too much though and the next dangerous attack came from the visitors.
Freddie Sears nicked the ball from centre half Wright before making strides down the right. He waited for support and as Sanchez Watt made the box, Wiseman had to get there first to prevent the low cross reaching the former Arsenal man.
It was Sears’ fellow forward Rhys Healey with the next chance, on fifteen minutes, one that he made no mistake with after the ball came back off keeper Jamie Jones.
Alex Gilbey made a driving run forward from the halfway line, exchanging passes before his shot was deflected, wrong footing Jones, who could only push the ball into Healey’s path – Healey put it in the net to make it 1-0.
The lead only lasted five minutes though, with full back Scott Wiseman getting forward to level things up.
He went past Watt too easily, before hitting a shot with the outside of his right foot low past Walker in the U’s goal.
It got worse for the U’s on twenty five minutes, as Alan Browne slammed home from inside the box, giving Walker no chance.
Ben Gordon was caught by the pressing Preston forwards and after Humphrey blocked away attempt to clear, Browne was on hand to make it 2-1 to the Lilywhites.
Conceding two goals in quick succession didn’t unsettle the U’s too much and Jones had to shuffle across his goal quickly to save with his legs from Watt’s header.
A patient build-up by the hosts ended with the ball at Gallagher’s feet but the shot went narrowly over the U’s crossbar.
Having created the opener, Gilbey scored a goal of his own nine minutes from half time, a cracker from outside the box that gave Jones no chance.
A topsy turvy half almost had another twist at the end, as Freddie Sears’ shot went just over the top of the bar in injury time.
The home side gave their partisan crowd something to cheer very early on in the second half, going 3-2 ahead within a couple of minutes.
Gallagher took aim from distance and Walker will be very disappointed that he failed to get his hands behind the ball and prevent it going past him and into his net.
Once again, the U’s didn’t let the disappointment of a goal get them down and they were straight back at their hosts.
Moncur picked the ball up just outside his own penalty area and ran eighty yards forward before hitting his effort tamely at Jones in the home goal.
On fifty minutes, Buchanan hit the post with a speculative effort, the first of three home efforts to hit the woodwork.
Just before the hour mark, the home side gave themselves a two goal cushion as Humphrey timed his run to perfection and toed the ball past walker before finishing into the empty net.
Gavin Massey had a long range effort comfortably saved by Jones before Garner’s clever lobbed header came back off the U’s bar.
On sixty five minutes, Tony Humes made his first change as he bought on Drey Wright for loanee Healey.
A minute later, Watt drilled a dangerous ball across the six yard box into the path of Sears but before the ball reached the U’s striker, a defender slid the ball to safety.
The third strike of the U’s woodwork came in the seventy fourth minute, with sub Callum Robinson curling his effort just inches too high.
Watt had the ball in the home net with eight minutes remaining, but he was flagged offside well before he netted at the second attempt after Sears’ shot was saved.
The U’s were still battling to get back into the game in the late stages but Sears and Gilbey were both denied by Jones in the final five minutes.
The referee’s whistle went after three minutes of uneventful time added on, with the U’s rueing an uncharacteristic defensive display under Humes.
There was plenty of flair and inventiveness going forward but Preston had quality that punished the errors made defensively.
There is a break from league action on Tuesday, as the U’s host Gillingham in the second round of the Johnstone’s Paint Trophy.