Following a quiet first half from both sides which the visitors perhaps edged, Christian Ribeiro swept his side ahead on the hour mark.
Karl Hawley then added a second ten minutes later before Kevin Lisbie pulled one back from the penalty spot for the O's.
Nevertheless, Damien Mozika soon added a third as the Iron celebrated victory.
The away side Iron entered the game making two changes from the side beaten by Bournemouth a week earlier.
Captain Paul Reid returned from a three-match suspension to replace Mark McChrystal at the heart of defence, while Michael Collins came into the side in place of Mike Grella as Scunthorpe played Hawley up front on his own.
Steve Mildenhall started in goal, with Ribeiro, Reid, Niall Canavan and Tom Newey forming the defence.
The midfield consisted of Mark Duffy, Mozika, Jimmy Ryan
, Collins and Andy Barcham, while Hawley led the attack.
The substitutes were McChrystal, Grella, Callum Kennedy, Adda Djeziri, Robbie Gibbons, Matt Godden and Sam Slocombe.
The game got off to a fairly slow start as both sides cancelled each other out in a scrappy opening.
Chances were few and far between, and the first time a goalkeeper was really called into action was on 17 minutes when Ryan Allsop stopped low to catch a powerful Duffy cross.
As the game reached the half hour mark, there had still not been a proper shot on goal as the two respective defences continued to clear their lines efficiently and stay solid.
The first real opportunity of the match arrived in the 35th minute as Ryan found space and unleashed a stunning long range effort which just missed the top corner of the net, flying over.
Then, two minutes later, the same player struck a volleyed effort which Allsop had to get down well to stop.
The hosts got in the Iron box for the first time in the 38th minute when Lee Cook dribbled his way through but he rushed his shot and fired wide.
Allsop was drawn into another stop just before half-time when Duffy's effort from just inside the area stung his fingers but was caught.
Leyton Orient came out of the traps alot livelier in the second period, and they put a succession of crosses into the box, pinning the visitors under some early pressure.
In the 53rd minute, Dean Cox came within a whisker of putting the hosts ahead, but his shot from 18 yards went just wide.
There was a brief moment of respite for United two minutes later when Duffy tried to clip a throughball for Hawley, but the striker just failed to get on the end of it.
Scunthorpe, who had taken the sting out of the game a little, went ahead in the 61st minute when Ribeiro drove forward into the area and drilled the ball between the goalkeeper's legs for his second goal of the season.
Orient tried to force their way back into the game but their play became scrappy and United were easily mopping up what was sent to them.
On 69 minutes, Hawley made it two. Duffy's clever pass from a free-kick sent the marksman clear, who rifled a low drive across Allsop and into the back of the net.
That seemed to make the away team comfortable, and the next chance was on 75 minutes when Duffy's free-kick just cleared the crossbar.
The woodwork was then struck just a minute later as Hawley connected with a Ribeiro cross but his stinging volley clipped the top of the crossbar and went over.
However, the home side were rewarded a lifeline in the 78th minute when Ribeiro was penalised for handball in the box after a cross-shot struck him.
And Kevin Lisbie stepped up to slam the ball past Mildenhall and seemingly make the final 12 minutes difficult for Scunthorpe.
Nevertheless, just two minutes later, the two goal advantage was restored as Newey's cross was flicked on by Barcham, who found Mozika, whose shot was deflected into the back of the net for his second strike of the season.
There was a United substitution three minutes from the end as Ryan was replaced by Djeziri.
There were four minutes of stoppage time played but United held on for an all-important league victory.
Scunthorpe are next in action on Saturday when they host Carlisle United in their centenary match.
Allsop; Odubajo, Chorley, Baudry, Sawyer; Cox, Rowlands (A Smith, 79), James, Cook (McSweeney, 70); Lisbie (Brunt, 89), Mooney.
Jones, Cuthbert, Griffith, J Smith.
Mildenhall, Ribeiro, Reid, Canavan, Newey, Duffy, Mozika, Ryan (Djeziri, 85), Collins, Barcham, Hawley.
Grella, Kennedy, Gibbons, Godden, McChrystal, Slocombe.
4,942 (341 away).