Second half goals from David Mooney and substitute Kevin Lisbie consigned Latics to their first defeat in 11 league games.
Jonathan Forte had given Latics the dream start, firing past the goalkeeper to give the home side the lead on 15 minutes, but that lasted only five minutes as Darius Henderson equalised.
Mooney and Lisbie grabbed the goals in the second half as Latics still search for their first victory of the season.
Latics started the game brightly, keeping the ball well and pressing high up the pitch.
That pressure paid off on 15 minutes as Forte gave the home side the lead. Midfielder Carl Winchester, who had an impressive first half, played the striker through and he made no mistake, sliding the ball past Adam Legzdins in the Leyton Orient goal to make it three goals from two games.
That lead lasted all of five minutes as Henderson equalised for the visitors. The striker beat the offside trap and slipped the ball underneath Paul Rachubka to level the scores.
Latics did not let that goal affect them and went in search of another. Joseph Mills fed Forte, who laid the ball back for the onrushing Mike Jones but he scuffed his effort wide of the post.
Only a minute later, Latics had to be aware defensively as defender Mathieu Baudry snuck in at the back post but George Elokobi, who was making his first league start for Latics, cleared off the line to keep the scores level.
As half time approached, the home side continued to attack. Jonson Clarke-Harris' turn of pace took him round the last defender and he crossed for Liam Kelly but the captain miscued his header and his effort went wide.
Just before the break, Clarke-Harris was brought to the ground for a Latics free kick but Mills' set piece was comfortably saved by Legzdins.
The visitors started the second half on the front foot with Dean Cox and Henderson linking well in attack.
The two combined for Orient's second goal of the game on 58 minutes as Henderson laid the ball through to Mooney and he tucked the ball away on the angle giving Rachubka no chance.
Clear-cut chances were proving hard to come by for the home side as Orient's defence were staying resolute.
Latics' main threat was coming from corners and Elokobi rose highest on 65 minutes but his header evaded the crossbar.
James Dayton and new signing David Noble were introduced into the game but it was O's substitute Lisbie that extended their lead on 81 minutes.
The striker headed home a corner at the back post to end any signs of a Latics comeback and gave Lisbie his first goal of the season.
As the minutes ticked down, Elokobi again rose highest from a cross into the box from Dayton but the defender's tame header went wide.
Played in front of 3,754 supporters, Latics lost their 11-game unbeaten streak and face Port Vale on Tuesday back at SportsDirect.com Park looking for a response.
Oldham Athletic: Rachubka, Brown, Elokobi, J.Wilson, Mills, Dieng (Philliskirk 63'), Kelly, Jones, Winchester (Dayton 79'), Forte, Clarke-Harris (Noble 79').
Subs not used: Coleman, Gros, Mellor, Kusunga.
Leyton Orient: Legzdins, Vincelot, Cuthbert, Baundry, Cox, Mooney, Lowry, Clarke, Pritchard, Henderson (Lisbie 80'), Simpson (McAnuff 66').
Subs not used: Omozusi, Sawyer, James, Lee, Woods.
Goals: Oldham Athletic (Forte 15') 1-3 Leyton Orient (Henderson 20', Mooney 58', Lisbie 81')
Attendance: 3,754 (193 visiting fans)