The match was only five minutes old when Exeter made the breakthrough as Tom Nichols scored from the penalty spot before Orient fell two behind through Alex Nicholls' 37th minute strike.
Nichols then added his second from another penalty ten minutes after the restart before David Wheeler bagged Exeter’s fourth to complete a disappointing afternoon for Orient.
For the trip to St James’ Park, Leyton Orient made two changes to the side that defeated Bristol Rovers the previous weekend as Charlie Grainger made his League debut in the O’s goal, while Alan Dunne replaced Frazer Shaw who dropped to the bench.
Ahead of the match Orient had yet to concede first in any of their opening five League Two fixtures, but by the fifth minute that record was to be broken.
A ball down the right of the O’s defence found its way to Exeter striker Tom Nichols who managed to brush off Mathieu Baudry to enter the penalty area, where he then managed to get a touch on the ball before being brought down by Orient goalkeeper Charlie Grainger resulting in a penalty being awarded.
Nichols then picked himself up to take the spot-kick and, despite Grainger guessing the correct way, opened the scoring with a shot low to his right.
It was far from the start Ian Hendon’s side had in mind but following the goal Orient gradually grew into the game.
A neat passing move for Orient then saw Bradley Pritchard produce a good turn on the edge of the penalty area but despite there appearing to be contact as he entered the box, any penalty appeals were waved away by referee Kevin Johnson.
Pritchard was finding himself at the thick of the majority of Orient attacks and moments later the midfielder sent a shot over the bar from 20-yards out.
With the match swinging in the O’s favour Dean Cox then delivered a teasing ball across goal which was calling out for Paul McCallum to touch home but Exeter defender Troy Brown was on hand to touch the ball out for a corner.
From the ensuing corner Orient had looked to pulled level when Cox’s delivery was headed back across goal by McCallum. With Olejnik out of his goal Jay Simpson then turned the ball goalwards but Grecians’ skipper Matt Oakley was able to clear off the line.
Despite having enjoyed the brief pressure Orient’s 100 per cent League record was put in real danger eight minutes before half-time as Exeter doubled their lead.
Having failed to clear an Exeter corner the ball dropped to the feet of Ryan Harley who picked out Alex Nicholls on the edge of the penalty area for the midfielder to take a touch before rifling a left-footed shot through the crowd and beyond Grainger.
Exeter’s second saw Orient go into the break behind in a League Two fixture for the first time this season, leaving them with an uphill struggle.
Following the restart Hendon’s side looked to try and find a way back into the match but on the 55th minute conceded a second penalty of the afternoon when the already booked Alan Dunne tangled with David Wheeler.
Dunne avoided picking up a second yellow card but the O’s fell even further behind as Nichols drilled the penalty down the middle to make the score 3-0.
Immediately following the goal Blair Turgott was brought on in pace of Sammy Moore as the O’s reverted to a flat 4-4-2.
As the match entered the final third the hosts showed little signs of letting their lead slip and with 66 minutes played came agonisingly close to adding a fourth when Harley crashed a 20-yard shot off the bar.
Nichols then looked to be set to complete his hat-trick as he ran onto the rebound but was denied by a superb stop from Grainger as he kept his attempt out with his right leg.
With Dunne on a booking forward Scott Kashket came on as his replacement for the final 20 minutes as the O’s went to three at the back.
Turgott then had a chance to pull a goal back for the visitors as the ball dropped to him unmarked to the right of the penalty area but despite making a good connection with his shot it was blocked by Exeter defender Jordan Tillson.
With 13 minutes remaining Orient’s bad day was then compounded as the hosts added a fourth.
A powerful shot from Harley was well saved by Grainger but Connor Essam could only send his header straight into the path of David Wheeler who set himself before rolling a low shot in off the far post.
The defeat saw Orient slip to their first League defeat of the season as they now look to bounce back at Cambridge United next weekend.
EXETER: Olejnik, Ribeiro, Tillson, Brown, McAllister (Woodman 78), Oakley (C), Harley, Nicholls, Noble (Oyeleke 87), Nichols, Wheeler (McCready 83)
SUBS: Butterfield, Morrison, Reid, Pym
GOALS: Nichols (5 pen, 56 pen), Nicholls (37), Wheeler (77)
BOOKINGS: McAllister (24)
ORIENT: Grainger, Clohessy, Baudry (C), Essam, Dunne (Kashket 68), James, Pritchard, Moore (Turgott 58), Cox, McCallum (Palmer 75), Simpson
SUBS: Sargeant, Shaw, Maguire, Payne
BOOKINGS: Dunne (46), McCallum (48), Pritchard (87)
Referee: Kevin Johnson
Attendance: 3,648 (505 Orient fans)