Jack Marriott scored the only goal of the afternoon midway inside the first half as Orient dropped out of the Play-Off places.
Having claimed a draw at Carlisle on Tuesday night, player-manager Kevin Nolan made two changes to the starting XI as influential substitutes Sammy Moore and Ollie Palmer were rewarded with starts.
The O’s were also boosted by the return of Jobi McAnuff and Armand Gnanduillet who were both named amongst the substitutes.
A tight start to the game saw neither side really gain control throughout the early proceedings, and it was not until the 18th minute that Luton’s Jack Marriott had the first shot of the game as he fired wide from outside the box.
O’s top goalscorer Jay Simpson then looked to make the breakthrough five minutes later from a short corner routine, but his effort curled wide of the visitors’ goal.
Marriott was to convert with his next chance however, as on the 27th minute the striker put the Hatters ahead, placing a lob over Alex Cisak after Shaun Brisley had failed to get a touch on Craig Mackail-Smith’s flick-on.
With just over 30 minutes played there was a lengthy delay to proceedings when Luton goalkeeper Jon Mitchell caught Brisley in the face as he punched away a ball into the box.
The collision resulted in Brisley needing several minutes of treatment on the pitch before being stretchered off and replaced by Jobi McAnuff.
McAnuff’s introduction saw the O’s shuffle the pack defensively, as Sean Clohessy moved back to right-back and Nicky Hunt moved across to partner to Mathieu Baudry in defence, and the winger nearly made an instant impact with a shot that was easily gathered.
The match was turning into quite a fiery affair in the middle of the pitch, and referee Charles Breakspear found himself awarding several free-kicks for late challenges throughout the final minutes of the half.
As the half entered the final minute of normal time, Ollie Palmer was presented with a wonderful chance to equalise for the hosts when Sammy Moore delivered a great cross into the box, but the forward was unable to keep his header down as it dropped over the bar.
Following seven minutes shown by the fourth official, defender Jerome Binnom-Williams worked an opportunity with a fine piece of individual skill, but after beating two men his shot with the outside of his boot was held by Mitchell.
Following the interval the O’s returned for the second half unchanged, but were left frustrated during the early part as Luton cleared a number of crosses pumped into their box.
Orient were continuing to push forward in search of an equaliser, and with just over an hour played they made their second substitution as Armand Gnanduillet replaced Palmer.
There were then huge cries for a penalty on the 65th minute when McAnuff went down insdie the box, but the referee was having none of it and waved the appeals away.
Less than a minute later it should really have been 2-0 to Luton but full-back Dan Potts curled a right footed effort agonisingly wide of the far post despite having space on the edge of the area.
Calaum Jahraldo-Martin was then brought on for the O's final change in place of Sammy Moore, but Luton continued to stand firm and frustrate the hosts, with former Orient defender Scott Cuthbert producing a fine piece of defending to clear Clohessy's cross behind on the 75th minute.
Despite continuing to press Luton back the hosts were struggling to trouble Mitchell between the sticks, with Gnanduillet coming cloesest with a shot from outside the box which was comfortably held.
As four minutes stoppage time was shown Orient then had a second appeal for a penalty turned down as Gnanduillet looked to be tripped, but once again any appeals were ignored.
Baudry then joined the attack for the final minutes but Orient were unable to grab an equaliser as Luton held on.
The defeat sees the O's drop outside of the Play-Off places and down to 8th ahead of their trip to Oxford United next weekend.
ORIENT: Cisak, Hunt, Baudry (C), Brisley (McAnuff 37), Binnom-Williams, Clohessy, Atangana, Nolan, Moore (Jahraldo-Martin 68), Simpson, Palmer (Gnanduillet 61)
SUBS: Grainger, Essam, Pritchard, Payne
LUTON: Mitchell, O’Donnell, Cuthbert (C), Sheehan, Potts (Okuonghae 87), Lee, Smith, McGeehan, McCourt (Ruddock-Mpanzu 65), Mackail-Smith, Marriott (Green 77)
SUBS: Justham, Lawless, Benson, Pigott
GOALS: Marriott (27)
BOOKINGS: O’Donnell (30), Mackail-Smith (89), Mitchell (90+2)
REFEREE: Charles Breakspear
ATTENDANCE: 5,684 (1,402)