Dan Kemp’s strike just before half time saw Orient go into the break level, however a three goal second half onslaught from The U’s ensured they secured the three points.
Interim Boss Jobi McAnuff made one change from the weekend victory over Barrow, as Ouss Cissé returned to the side in place of Craig Clay.
Needing a result to keep their playoff push on track, The O’s made a positive start in E10. Top scorer Danny Johnson raced away from the visitor’s backline and from an acute angle unleashed a rasping effort that U’s ‘keeper Callum Burton did well to turn away.
The good start continued moments later as Conor Wilkinson laid the ball off to Louis Dennis on the edge, the former Portsmouth man then flashed a strike just wide of Burton’s far post.
Orient came even closer on the 15-minute mark. Johnson again caused problems for the Cambridge defence as he found space in the box and got a shot off that Burton did excellently to force behind.
Against the run of play, The U’s took the lead through Joe Ironside. Jack Iredale found space down the left and crossed it low into the area for the forward, who then fired low and hard past Lawrence Vigouroux.
Buoyed by their opener, Mark Bonner’s side began to take control and managed to create a couple of decent opportunities, however both Shilow Tracey and Hiram Boateng blazed their efforts off target.
Just before half time, McAnuff’s side found a leveller. The visitors defence failed to deal with an inviting ball into the box from Dennis and after a period of pin ball in the box, Dan Kemp was on hand to power home an equaliser from close range.
The second half started at a ferocious speed. First, Dennis almost got a shot away in the Cambridge box but was crowded out, then, from the breakaway, Vigouroux had to be on alert to tip Boateng’s shot over.
As the tempo slowed down and the clock ticked past the hour mark, McAnuff elected to make his first change of the evening. Clay the man chosen to enter the fray for Hector Kyprianou in the heart of midfield.
Shortly afterwards, the away side regained the lead. Vigouroux did well to keep out Greg Taylor’s initial header from a corner kick, however Tracey was on hand to turn in the rebound.
Bonner’s side extended their lead soon after. Referee Declan Bourne adjudged Jamie Turley brought down his man from a corner and pointed to the spot. Mullin then made no mistake with his penalty.
The O’s weren’t going to go down without a fight, however. James Brophy delivered a deep cross from the left-hand side towards Wilkinson, the former Gillingham man met the delivery well and saw his header cannon off the post and onto Declan Drysdale and into the net for an own goal.
But Cambridge’s two goal lead was restored in the 79th minute when Turley’s throw in was intercepted by Ironside and the forward crashed in his second of the game.
Orient huffed and puffed but were unable to find a way back into the contest, as they fell to their first home defeat since McAnuff took interim charge back in March.
ORIENT: Vigouroux, Akinola, Turley, Happe, Brophy, Cissé (McAnuff 80’), Kyprianou (Clay 62’), Wilkinson, Kemp, Dennis (Sotiriou 80’), Johnson
SUBS: Sargeant, Widdowson, Coulson, Freeman
BOOKED: Johnson, Turley, Akinola
GOALS: Kemp 45’, Drysdale OG 72’
CAMBRIDGE: Burton, Knoyle, Iredale, Digby, Taylor, Drysdale, Hannant, Mullin (O’Neil 90’), Tracey (Dunk 64’), Ironside, Boateng (May 90’)
SUBS: McKenzie-Lyle, O’Neil, Okendina, Alese, Neal
GOALS: Ironside 19’, Tracey 64’, Mullin 68’, Ironside 79’
REF: Declan Bourne