David Wheeler put the Grecians ahead with just four minutes on the clock, before a second half double from Ryan Harley, one from the penalty spot, and a late effort from substitute Liam McAlinden sealed the defeat.
O’s boss Andy Edwards made three changes to the side which drew 1-1 with Cambridge United as injured trio Teddy Mezague, Sandro Semedo and Sam Dalby all missing out with Yvan Erichot, Callum Kennedy and Ollie Palmer coming in respectively.
Chances came early on for both sides as Paul McCallum’s header was denied by Christy Pym, before Reuben Reid fired an effort straight at Alex Cisak.
The deadlock was broken though four minutes in as David Wheeler nipped in and slotted past Cisak to give the hosts an early advantage.
Their lead could have been shortlived though as some neat build up play involving Palmer and McCallum ended with the latter heading Massey’s cross back across goal, though no-one was able to get on the end of it.
The Grecians were enjoying plenty of possession in the final third and Ollie Watkins was close to adding a second when found by Reuben Reid’s pull back from the byline.
Watkins continued to be a threat for the hosts and was found again via a throughball. He outpaced Judd before getting a shot away but Cisak was to the rescue in the O’s goal to keep the effort out.
The striker was to find the back of the net in the 19th minute but the effort was rightly ruled out for offside as the O’s were cut open once more.
Orient still looked dangerous down the right and after Hunt found Massey, the winger laid the ball back into the path of Judd whose first time cross was headed goalwards by McCallum, only for Pym to keep it out.
Exeter made a quick break from that though and the ball was played through for Watkins who had the beaten of everyone apart from the post, before Parkes was forced to clear off his line after the rebound ricocheted off the central defender.
Chances were few and far between for the O’s but Massey was the one constant threat. This time he done well to control a ball in the box, before he flashed an effort wide of Pym’s far post.
Before the half was out though Cisak was forced to punch behind a fierce header from Wheeler from former O Lloyd James’ corner.
No changes were made at break, but Orient were quickly on the defensive as the Grecians asserted the early pressure. Watkins went down in the box under a challenge from Parkes, but referee Michael Salisbury waved play away.
The second for the hosts didn’t take too long in coming though when David Wheeler’s fine cross from the right was met by an unmarked Ryan Harley who slotted home.
Josh Koroma was brought on just before the hour mark as a replacement for Callum Kennedy as the O’s looked for a way back into the encounter.
That looked even more unlikely though when Tom Parkes was adjudged to have brought down Ollie Watkins just inside the box, despite protests of the foul initially taking place outside the area.
Harley stepped up to take the spot kick and although Cisak went the right way he couldn’t keep the effort out.
Judd and Massey linked up well down the right as they so often have of late, and the latter’s ball into the box was put behind for a corner which came to nothing as Massey fired over following an Exeter clearance.
Koroma gave the O’s option down the left and a lovely run found the youngster whose cross was marshalled clear by Troy Brown.
He again continued to be the one positive to take from the game as with less than 10 minutes to go he produced a mazy run across the pitch before firing just over.
O’s woes increased further though as Atangana’s weak back pass was intercepted and substitute Liam McAlinden slotted past an onrushing Cisak.
Robbie Weir’s afternoon, having come on as a substitute, was brief as he was forced off on a stretcher and was replaced by Victor Adeboyejo.
The game ended on that sour note, and boss Andy Edwards will look for a big response from his players in Saturday’s home game with Barnet.
EXETER CITY: Pym, Woodman (Archibald-Henville 83), Moore-Taylor (c), Brown, Stacey, Harley (Simpson 74), James, Tillson, Wheeler, Watkins, Reid (McAlinden 63).
SUBS: Olejnik (GK), Taylor, Ampadu, Sweeney
GOALS: Wheeler (4), Harley (50, 65), McAlinden (82)
ORIENT: Cisak, Judd, Parkes, Erichot , Hunt (c), Massey, Atangana, Collins, Kennedy (Koroma 59), Palmer (Weir 73 (Adeboyejo 87)), McCallum.
SUBS: Sargeant, Bowery, Pollock, Ochieng.
REFEREE: Michael Salisbury
ATTENDANCE: 4,537 (259 Leyton Orient fans)