United boss Sir Alex Ferguson reportedly chose to watch Champions League opponents Valencia instead, leaving Mike Phelan in charge, and there was plenty for the assistant manager to think about as Scunthorpe were rewarded for their terrific start by Josh Wright's superb 19th-minute strike.
But it took only four minutes for Darron Gibson to level and they were ahead before half-time through Chris Smalling.
Two goals from Michael Owen and one from Park Ji-sung in the second half put the result beyond doubt but Scunthorpe got the second goal they deserved in injury time from the impressive Martyn Woolford.
Phelan made 11 changes to the side that beat Liverpool 3-2 on Sunday but it was by no means a weak team, with Rio Ferdinand, Owen, Anderson, Wes Brown, Park and Javier Hernandez all in the starting line-up.
It was the first competitive meeting between the sides and Scunthorpe were determined not to let the chance to upset their illustrious opponents pass them by.
The hosts flew out of the blocks, with Woolford and Eddie Nolan testing Tomasz Kuszczak while Wright sent a fierce volley wide of the post.
United had not heeded the warning, though, and, when Woolford picked out Wright just outside the area in the 19th minute, the midfielder crashed a shot into the top corner.
It was no more than the hosts deserved but their lead lasted only four minutes as Phelan's side levelled out of nothing. A long ball from Smalling found Gibson down the right channel and he sent a pinpoint lob over Joe Murphy.
It was a stunning finish but it did not change the pattern of the game and Scunthorpe should have retaken the lead on the half-hour mark as Michael O'Connor's corner perfectly picked out captain Cliff Byrne at the far post but his header flew over the bar.
And United made their hosts pay in the 36th minute with their second goal. Brown picked up the ball on the right and played in Park, whose cross was coolly turned into the net by centre-back Smalling.
Still Scunthorpe pressed and they were inches away from levelling when Kuszczak again opted not to catch Jonathan Forte's 25-yard effort and could only watch as his punch nearly took the ball inside the far post.
Javier Hernandez and Federico Macheda had been largely ineffective but they combined to good effect on the stroke of half-time, with the Mexican setting up his fellow striker for a header over, before Nolan forced Kuszczak to punch away another shot.
Scunthorpe were soon on the attack again in the second half and the United defence did well to block Byrne's diving header from Nolan's deep cross.
But the hosts' positive approach was leaving them vulnerable on the break, and four minutes after half-time Owen made them pay as he netted United's third.
Macheda looked like he had held onto the ball too long but in fact he timed his pass perfectly to release Owen and the former England striker made no mistake.
If that made Phelan breathe a little easier, he was surely able to relax five minutes later as Park tucked away a fourth goal. Anderson's corner was not properly cleared and the Korean had all the time he needed to drill a shot inside the post from 15 yards.
The scoreline, which was already harsh on Scunthorpe, got even more lop-sided in the 71st minute as Murphy parried Park's effort but only as far as Owen, who could not miss from five yards.
Then, with 16 minutes left, United fans were given a first glimpse of their new £7million man as Bebe replaced Park.
The 20-year-old was made to wait for his first touch of the ball, however, as a streaker was given the full run of the Glanford Park pitch for a couple of minutes before finally being tackled by stewards.
The unscheduled interruption also saw a number of United fans throw bottles onto the pitch as they were taunted by the Scunthorpe supporter.
When play resumed, Bebe made his mark with a run and fierce shot that was deflected behind for a corner, while Macheda thought he had made it six but he was denied by the offside flag.
Scunthorpe were now playing for pride but they came within inches of a second goal twice in a minute as first Kuszczak pushed away substitute Bobby Grant's free-kick before Byrne headed just wide.
The Polish keeper then made his best save of a busy night, tipping over Grant's long-range shot, and from the injury-time corner Scunthorpe finally put the ball in the net, and it was fitting that the last word went to Woolford.