Having had the better of the first half, they looked well placed to push on in the second half against a home side who were looking to impress any potential new managers watching in the stands.
But Kevin Keen's men were left to rue the fact that their territorial edge in the first half was not converted into goals as a quick fire treble saw the game taken away from them around the hour mark.
The U's boss introduced Joe Edwards into the starting eleven, coming in in place of Gavin Massey.
The midfielder was full of energy in the opening forty-five, as he symbolised a hard working first half display.
The U's made the most of some nerves and loose play by the home team on a number of occasions in the first half but, due to the defensive fortitude of centre halves Murray Wallace and David Mirfin, they found a clear route to goal hard to find.
Both defenders blocked numerous chances, with Gilbey denied on 21 minutes by one strong challenge.
Three minutes later, Porter knocked down to Moncur, whose left footed effort went just over the crossbar.
Edwards then saw Mirfin out to block on 27 minutes from a fine half volley, before Moncur had a similar effort seen away at the far post.
Just before half time, the U's bench were appealing for a handball as a cross popped up onto the extended arm of Mirfin, but the referee showed little interest.
Having been off the pace in the first half, it was perhaps no surprise that Scunthorpe were improved after the break.
They scored three in eight minutes as first Hopper slid home under Kean, before Madden's shot against the underside of the bar was adjudged to have crossed the line by the linesman.
And Madden, so often the thorn in the U's side in the past, made it three as he drilled a low shot past Kean as the U's defensive discipline slipped again.
From there, as much as the visitors probed, they couldn't find their way past Wallace, Mirfin and co and were left to lick their wounds once again.
The FA Cup awaits - and what a day it will be - but the U's players will no doubt be chomping at the bit to get back to the league and a crunch derby clash at Southend.