Despite dominating large parts of the first half, Scott Wilson headed home to send the visitors into the lead at the break, and it proved to be the winner as Orient failed to find a way back following the restart.
Head Coach Steve Davis made one chance to the starting XI that who defeated Dagenham & Redbridge in the FA Cup on Tuesday night.
Mark Ellis replaced Michael Clark in defence, while Jobi McAnuff and Alex Lawless missed out through groin injuries.
Orient got the game underway after a 20-minute delay to kick off due to strong winds damaging advertising on the North Stand, and just inside the opening ten minutes Ellis struck an effort wide of the target to register the first attempt on goal.
A forward ball from Dan Happe released Macauley Bonne through on goal, the striker took a touch before he went down under a challenge from ‘keeper Shawn Jalal on the edge of the box but the referee waved play on.
As a result of the collision with Bonne, Macclesfied ‘keeper Jalal was replaced by Sam Ramsbottom after 19 minutes of play.
Happe’s initial shot from a corner fell at the feet of David Mooney whose attempt to help the ball over the line is blocked at point blank range by Ramsbottom.
Seconds later, Jake Caprice darted down the wing and crossed to the back post where Myles Judd was positioned to head in, but the defender’s effort was gathered by the ‘keeper.
As the half hour mark approached it was all one-way traffic, Judd found space on the left to swing a ball intowards Mooney, the striker then powered a header towards goal but Ramsbottom plucked the ball out of the air.
A rare chance for Macclesfield saw Danny Whitehead try his luck from distance, but Charlie Grainger was equal to it and pushed the shot away from danger.
Seconds later however, the visitors took the lead, a whipped cross into the box saw Scott Wilson in the right place to head home.
Soon after the restart, Mooney couldn’t get a clean connection on the end of Judd’s pass into the box from close range.
Three minutes after the hour mark, James Dayton’s cross was met by the head of Bonne but his header is palmed into the air by Ramsbottom, Mooney then collected the rebound but the ‘keeper again made the save to deny the captain the equaliser.
Dayton fired a volley towards goal from just inside the box but the ball was parried behind for a corner by the high flying Ramsbottom.
As the O’s pushed for a leveller, the visitors broke free on the counter. Wilson raced towards goal with Grainger to beat but the striker fired high over the target.
With Macclesfield sitting deep the O’s continued to search for an equaliser during five minutes stoppage time, but were unable to find a way through as they slipped to defeat in E10.
ORIENT: Grainger, Caprice, Ellis (Westbrooke 59), Happe, Widdowson, Judd, Clay, Boco (Brophy 59), Dayton, Mooney (C) (Sotiriou 69), Bonne
SUBS: Sargeant, Clark
BOOKED: Clay (90+5)
MACCLESFIELD TOWN: Jalal (Ramsbottom 19), Fitzpatrick, Lowe, Pilkington, Durrell, Wilson (Marsh 76), Lloyd, Kennedy, Hancox (Arthur 81), Whitehead, Whitaker (C)
SUBS: Baba, Burgess,
GOAL: Wilson (45 +1)
BOOKED: Pilkington (25), Whitehead (85), Durrell (88)
REFEREE: Christopher O’Donnell
ATTENDANCE: 4,562 (193)