After a hard-fought opening forty-five minutes Town were well-placed to get something from the game but conceded twice in quick succession to Aaron Drinan shortly after the break with a Ruel Sotiriou strike fifteen minutes from time capping the O's evening
Simon Weaver opted to bring Luke Armstrong straight back into the line-up following his one-game suspension. Town's leading scorer replaced Jack Muldoon who dropped down to the bench, where there was also a welcome return for Will Smith.
Richie Wellens made two changes for the O's from the side that defeated Rochdale at the weekend. Otis Khan and Darren Pratley came into the starting eleven in place of Paul Smyth and Ethan Coleman.
Town had the first effort of note when a George Thomson in-swinging free-kick just evaded the attacking Rory McArdle.
McArdle was to go into the book moments later however after halting the progress of Ruel Sotiriou, when the O's playmaker was bearing down on goal.
Alex Pattison's sweeping move countered for Town on five minutes teed up Lewis Richards whose powerful drive was turned round the post by Lawrence Vigoroux.
Ryan Fallowfield beat the offside trap after ten minutes but found himself crowded out before he could get his cross away.
There was a huge let off for Town a couple of minutes later when Theo Archibald struck an effort at the second attempt that rebounded off Mark Oxley's near post.
Town were thankful to Oxley after 20 minutes when he raced from his line to smother the onrushing Sotiriou.
Simon Weaver was forced into a change after 25 minutes when Richards was forced from the action. The defender was replaced by Simon Power with Town forced into a formation change, switching from the back three to a 4-4-2.
The dangerous Sotiriou was again front and centre on the half hour mark when he fired narrowly over from the edge of the area.
With the first-half drifting towards its close Pattison's rasping drive created a spark but his right-footed effort skidded narrowly wide with Vigoroux beaten.
Barely five minutes of the second-half had elapsed before Town were behind. McArdle's headed clearance rebounded back into the danger zone and Drinan took possession, advanced to the edge of the area and held the Town defence at bay before firing past Oxley.
And Town quickly found themselves two-goals down courtesy of that man Drinan.
A long throw into the box was met by Omar Beckles and the big defender's flick-on was met first time by the O's midfielder for his 12th goal of the season.
Weaver responded by throwing on Saturday's hero Callum Kavanagh in place of Mark Beck.
The visitors almost stretched their lead further when another throw into the box evaded the Town defence but Sotiriou's lacked composure with his finish.
There was a flash of inspiration with twenty minutes when Jack Diamond weaved his way through the O's defence but his low cross was straight at Vigoroux.
Diamond had a clear cut chance moments later to reduce the arrears when neat play from Kavanagh and Power released him but he struck the post with his effort with Vigoroux rooted to the spot.
Pattison then struck straight at Vigoroux before Town fell further behind when McArdle's misplaced pace fell straight to Sotiriou who finished with aplomb past Oxley. That was the end of McArdle's evening as he was replaced by Smith.
Power then hit the bar from 12 yards out after Diamond's cut-back, which summed up Town's fortune in front of goal on the night.
Richie Wellen's then made a pair of changes, taking off Theo Archibald and goalscorer Drinan, introducing Paul Smyth and Matt Smith into the fray.
With a commanding lead the O's were content to play out the remainder of the game and it could have been even worse for Town in injury time when substitute Smith's effort rebounded off the post to safety.
TOWN: Oxley, Fallowfield, Burrell, McArdle (Smith, 77), Richards (Power, 30), Sheron, Thomson, Pattison, Diamond, Beck (Kavanagh, 58), Armstrong.
Subs not used: Cracknell, Austerfield, Muldoon.
Booked: McArdle (2), Sheron (90)
Leyton Orient: Vigoroux, Wood, Thompson, Archibald (Young, 80), Khan, Drinan (Smith, 79), Pratley, Beckles, Sotiriou (Smyth, 76), Ogie, Kyprianou.
Subs not used: Sargeant, Smyth, Smith, Nouble, Young, Coleman, Ray.
Goals: Drinan (51, 57), Sotiriou (75)
Referee: Ross Joyce.