Ben Williamson had given the U's a 10th minute lead after pouncing on a loose backpass, and doubled his tally for the afternoon eight minutes after half time.
Subsitute Armand Gnanduillet then scored his first goal for Orient to pull a goal back on the 57th minute, but the U's added a third six minutes later when Williamson turned provider for Jimmy Spencer to slot home having just come on as a sub.
Having claimed back-to-back victories in his first two matches, player-manager Kevin Nolan named an unchanged side for the third consecutive match. New signing Shaun Brisley was named on the substitutes bench along with the returning Sammy Moore.
The O’s had recorded clean sheets in the wins over Wycombe and Newport, but following a slow start to the match were denied any chance of a third on the bounce when Ben Williamson pounced on Frazer Shaw’s underhit backpass to knock the ball round Alex Cisak and slot into an empty net.
Cambridge had certainly benefitted from a real gift to make the breakthrough, and in response to the goal Orient skipper Mathieu Baudry headed Jobi McAnuff’s corner just over the bar.
Despite Baudry’s chance the hosts failed to really get in the swing of things throughout the first half, having several nearly moments only to see the final ball come to nothing, and as a result went into the break a goal behind.
With both sides opting against any changes at the break, O’s top scorer Jay Simpson latched on to Ollie Palmer’s knockdown but despite making a sweet connection saw his shot blocked bravely by the head of a U’s defender.
Despite the early chance the hosts then found themselves two behind on the 53rd minute, as Williamson outmuscled Connor Essam in the corner before cutting into the penalty area and beating Cisak at his near post.
Armand Gnanduillet was brought on in response to the goal, and the January recruit made an instant impact by halfing the deficit moments later, poking home his first goal for the Club after Jobi McAnuff’s corner had caused a scramble in the six-yard box.
However, Cambridge did not wait long to restore their two-goal lead when lively Williamson broke away down the right before unselfishly choosing not to go for his hat-trick by rolling the ball to substitute Jimmy Spencer to score with his second touch since coming on.
With just under 25 minutes left to play Kevin Nolan then replaced Jack Payne for the O’s final change.
The player-manager then won a free-kick straight after his introduction, and the ensuing ball into the box dropped to Gnanduillet who was denied a second by a fantastic last ditch block by Cambridge’s James Dunne.
Despite enjoying most of the possession throughout the final stages, it was not until two minutes of normal time remaining that Cambridge goalkeeper Will Norris was forced into a save, smothering Blair Turgott's low shot with several Orient players ready to pounce on a loose ball.
With the match well into stoppage time Baudry then picked out Nolan with a powerful header but the O's boss was unable to pull a goal back as he dragged his shot wide, proving to be the final piece of action as the O's slipped to defeat.
ORIENT: Cisak, Clohessy, Baudry (C), Essam, Shaw, Jahraldo-Martin (Turgott 58), Atangana, Payne (Nolan 67), McAnuff, Simpson, Palmer (Gnanduillet 53)
SUBS: Grainger, Brisley, Moore, Pritchard
GOALS: Gnanduillet (57)
BOOKINGS: Baudry (48)
CAMBRIDGE: Norris, Furlong, Legge, Coulson, Page, Donaldson (Spencer 61), Dunne, Ledson, Dunk (Simpson 82), Berry (C), Williamson
SUBS: Beasant, Omozusi, Roberts, Ahearne-Grant, Horne
GOALS: Williamson (10 & 53), Spencer (63)
BOOKINGS: Berry (29), Dunne (78)
REFEREE: Michael Bull
ATTENDANCE: 6,526 (1,237)