Ollie Palmer had got the O's off to a dream start by scoring inside the opening minute, but a goals from Jayden Stockley either side of Tom Nichols header saw the visitors go into the break with a healthy lead.
Jay Simpson then had two opportunities from the penalty spot in the final ten minutes, but was unable to convert either attempt as the O's fell to defeat.
Fresh from their two week lay-off it took the O’s less than a minute to make the breakthrough as the first attack of the game saw Jobi McAnuff clip the ball across for Ollie Palmer to simply chest the ball into an empty net.
Having taken an early advantage, the hosts continued to press forward and Blair Turgott squandered an opportunity to double the lead when he drilled a shot wide from 25-yards despite having Sean Clohessy in acres of space to his right.
Exeter were to make the most of that however as a minute later they found themselves level, thanks to former Orient loanee Jayden Stockley who managed to bundle the ball in at the back post from David Noble’s cross.
The equaliser had certainly knocked the visitors into gear and striker Tom Nichols was then presented with a great chance just shy of the 20th minute, but despite being clean through failed to find a way beyond Alex Cisak who superbly parried his shot away.
Nichols was not to be denied for much longer though as on the 23rd minute he benefitted from Alex Nicholls shot deflecting into his path to then direct a header goalwards which Cisak could only parry into his own net.
Soon after it should well have been 3-1 to Exeter as a ball forward saw Nicholls beat the offside trap and have the freedom of the O’s half to race into the penalty area, before opting to go alone and see his shot brilliantly tipped over by Cisak, much to the frustrations of the teammates unmarked to his left.
With 31 minutes on the clock Exeter then found the back of the net for a third time, when Danny Butterfield’s cross from the right dropped perfectly for Stockley to despatch a volley into the bottom right corner.
Looking for a way back into the match Turgott then had penalty appeals waved away and Palmer had a header comfortably saved by Grecians goalkeeper Bobby Olejnik, before the visitors were denied a fourth on the 39th minute when Christian Ribeiro’s curling shot from 20-yards crashed back off the crossbar.
Top scorer Jay Simpson had endured a tough first half in which he had seen little of the ball, but with the break approaching the striker came close as he directed a header narrowly wide of the far post.
It was clear to see something had to change during the break and O’s Head Coach Ian Hendon did exactly, that bringing on Frazer Shaw and Calaum Jahraldo-Martin in place of Jean-Yves M’voto and Turgott.
Following the restart Cisak had to be alert in the opening minute to deny Stockley his hat-trick, but it was then the O’s who came close twice inside the space of five minutes as Simpson first saw a shot bravely blocked before Bradley Pritchard’s cross was nearly turned into the Exeter net by Butterfield.
As Orient went in search of finding a way back into the game the visitors proved difficult to break down, though with 25 minutes remaining Clohessy’s shot could only be parried by Olejnik before the Grecians stopper gathered Palmer’s follow up.
With ten minutes remaining Orient were then awarded a penalty when Clohessy was brought down inside the box. Up stepped Simpson to take the spot kick, but despite sending Olejnik the wrong way his shot came back off the post.
Five minutes later Simpson then had a chance to make amends as he was brought down by Craig Woodman for another penalty, but this time the O’s top scorer saw his attempt pushed away by Olejnik.
The penalty misses summed up the hosts day as Exeter held on for the victory.
ORIENT: Cisak, Clohessy (C), M’voto (Shaw HT), Essam, Kpekawa, Turgott (Jahraldo-Martin HT), Pritchard (Kashket 82), Payne, McAnuff, Simpson, Palmer
SUBS: Grainger, Dunne, Moncur, Moore
GOALS: Palmer (1)
BOOKINGS: Pritchard (33), Payne (45+2)
EXETER: Olejnik, Ribiero, Brown, Moore-Taylor (C), Woodman (McAllister 88), Butterfield, Noble (Oakley 69), Nicholls, Holmes (Davies 86), Stockley, Nichols
SUBS: Hamon, Morrison, Hoskins, Tillson
GOALS: Stockley (14 & 31), Nichols (23)
BOOKINGS: Holmes (56), Nichols (74), Woodman (84)
REFEREE: Keith Hill
ATTENDANCE: 5,758 (529)