Unable to make the most of a strong first half showing Orient were punished after the break as Neal Bishop's deflected strike put Iron ahead and Jack King bundled home a second on the hour before Hakeeb Adelakun sealed the defeat in stoppage time.
The original meeting between the sides between the sides ten days ago at The Matchroom Stadium ended goalless and with a potential trip to Premier League champions Chelsea in the Third Round, O’s Head Coach Ian Hendon made three changes to the side that started at Mansfield on Saturday.
Frazer Shaw replaced the cup-tied Cole Kpekawa in defence, while Bradley Pritchard and Ollie Palmer also came in for Blair Turgott and John Marquis who dropped to the bench.
Keen to make an early impression on the match Orient created the first chance inside the opening minute, but top scorer Jay Simpson was unable to keep his composure as he rifled an effort into the top of the stand.
The hosts responded straight after however with a chance of their own when Charlie Goode’s delivery into the box was met by the head of Kyle Wootton though Alex Cisak was able to gather.
The O’s could be satisfied with their start to the match as they controlled large parts of possession, and with 11 minutes played were a whisker away from taking the lead when a goalmouth scramble dropped to the feet of Bradley Pritchard who had a shot deflected on to the post by the head of Goode before being cleared.
Moments later it was Scunthorpe who nearly broke the deadlock however when Wootton was brought down on the edge of the penalty area by Jean-Yves M’Voto to which Luke Williams then saw his effort deflected behind by Jack Payne.
As the half wore on Orient were winning a number of corners which looked to be causing Luke Daniels several problems and M’Voto first powered a header over the bar before the Iron goalkeeper was forced to push a Mathieu Baudry effort behind.
Although it was the visitors looking the more threatening in front of goal, the O’s were unable to make the breakthrough before half time as the sides went into the break goalless.
Following the break both sides came out for the second half unchanged and it was Scunthorpe who threatened early on when Scott Laird crashed a shot over from distance.
Iron captain Jack King then thumped a header over from a Williams corner on the 54th minute and a minute later the hosts made the breakthrough when Neal Bishop’s shot deflected off M’Voto to find a way beyond Cisak after Williams had intercepted a Sean Clohessy pass.
Five minutes later the O’s were then two behind when Williams corner caused a goalmouth scramble in the six-yard box and Iron skipper King was on hand to poke home from a yard out.
In need of a strong response Head Coach Ian Hendon then made a double substitution as he brought on Blair Turgott and John Marquis for James and Palmer for the final third of the match, before making his final substitution with just under 20 minutes remaining as Victor Adeboyejo replaced Jobi McAnuff.
Looking to find a way back into the tie Simpson then had a penalty appeal turned down following a blocked shot before Payne saw a lobbed attempt gathered by Daniels.
Hendon then threw M'Voto up front for the final few minutes but even a consolation was not forthcoming substitute Hakeeb Adelakun made it 3-0 to the hosts with a simple finish in stoppage time to end the O's FA Cup run.
SCUNTHORPE: Daniels, Wiseman, Goode, Canavan, Laird, Bishop, King (C), Madden, Ness (McAllister 78), Williams, Wootton (Adelakun 84)
SUBS: Anyon, Van Veen, Henderson, Boyce, Clarke
GOALS: Bishop (55), King (60), Adelakun (90+3)
ORIENT: Cisak, Clohessy, Baudry (C), M’Voto, Shaw, Payne, Pritchard, James (Turgott 63), McAnuff (Adeboyejo 71), Palmer (Marquis 63), Simpson
SUBS: Grainger, Essam, Dunne, Kashket
BOOKINGS: Palmer (45), Shaw (69)
REFEREE: David Webb