Andros Townsend stepped off the bench to hit a 57th-minute winner as Millwall's awayday blues continued.
Townsend had only been on the pitch for 50 seconds having replaced the injured Jason Demetriou when he capitalised on some sloppy defending to rifle home an angled drive past Lions keeper David Forde.
Kenny Jackett's men haven't won on their travels since Jason Price hit an injury-time winner at Crewe in March some 11 away games ago, and despite their effort, Millwall rarely suggested they would improve on that statistic.
In what proved to be a disappointingly scrappy derby, chances were few and far between the two sides as they both struggled to impress.
The Lions showed just one change to the team that had played so well against Huddersfield last Saturday with James Henry replacing Dave Martin, who dropped to the bench.
Former O's striker Gary Alexander also took his place on the bench after recovering from a heel injury, with Lewis Grabban the player making way.
The first half saw both teams try to prise and probe an opening, but the reality was that neither keeper really had anything other than standard saves to make.
Millwall's first serious foray after four minutes saw Ali Fuseini spread the ball wide to Steve Morison on the right, but his cross was just too close to home keeper Jamies Jones, who collected the ball comfortably.
Morison was involved again on 10 minutes with some smart footwork inside the area creating an opening for Jimmy Abdou 10 yards out. Unfortunately on this occasion the midfielder's shot lacked power and the danger was averted.
At the other end Luke Summerfield, signed on loan from Plymouth during the week, was close to marking his Orient debut with a goal after 17 minutes only to see a fierce left-foot shot deflected for a corner.
James Scowcroft wasted possibly the clearest opening of the half a couple of minutes later when he broke into the area, only to drill a shot wide on his weaker left foot.
Morison then headed wide following good work by Neil Harris and Tamika Mkandawire saw his effort glance over the bar as the two teams traded chances towards the end of a goal-less first half.
Millwall came out after the break showing greater intent and twice within the opening couple of minutes Harris first saw a trademark curler held by the keeper before then flicking the ball on to Henry, who drove over.
A clash of heads between Chris Hackett and Demetriou resulted in the O's midfielder leaving the field on 56 minutes. Within 50 seconds sub Townsend hit what proved to be the winner with his first touch of the ball, a rasping angled drive that gave Forde no chance.
Townsend was close to adding a second 10 minutes later when he escaped the attention of three Millwall players and let fly with a thunderous effort that Forde tipped over for a corner.
Jackett, who had already brought on Martin for Hackett, introduced former Brisbane Road favourite Gary Alexander and then Danny Schofield in quick succession in a bid to add some potency to his team's attack.
Harris teed up Alexander 18 yards out but keeper Jones was equal to Alexander's 81st-minute effort whilst Andy Frampton blasted over from close-range following a Martin corner.
But with the clock ticking away and The O's producing a resilient rearguard action, there was sadly to be no way back for Jackett and his men who will be determined to add points to the board with successive home games against Yeovil (Tuesday) and then Tranmere Rovers next Saturday.
Leyton Orient: Jones, Chorley, Mkandawire, Melligan, Demetriou (Townsend, 56mins), Daniels. Jarvis (McGleish, 76mins), Summerfield, Cave-Brown, Smith, Scowcroft. Subs not used: Morris, Ashworth, Pires, Baker, Patulea.
Booking: Melligan (90+3mins)
Scorer: Townsend (57mins)
Millwall: Forde, Dunne, Frampton, Fuseini (Schofield, 81mins), Ward, Smith, Henry, Abdou, Harris, Morison (Alexander, 71mins), Hackett (Martin, 64mins). Subs not used: Sullivan, Barron, Bolder, Laird.
Ref: Steve Tanner
Att: 5,255 (away 1,889)