Scunthorpe were made to pay for missed chances as a Gary Alexander double, as well as a late goal from ex-United man Jonathan Forte, proved the difference at the Broadfield Stadium.
The away side named an unchanged side from the team which won in the Capital One Cup at Derby County in midweek.
Sam Slocombe started in goal, with Christian Ribeiro, David Mirfin, Tom Newey and Callum Kennedy forming the defence.
The midfield consisted of Josh Walker, Jimmy Ryan, Mark Duffy and Andy Barcham, while Bobby Grant and Mike Grella led the attack.
The substitutes were James Severn, Mark Hughes, Jordan Keegan, Callum Howe, Connor Jennings, Robbie Gibbons and Niall Canavan.
The opening opportunity of the game arrived in the second minute when Gary Alexander scooped an effort over the crossbar.
The first Scunthorpe chance came just two minutes later when Ryan hooked a volley towards goal but saw it blocked away.
Then, Slocombe was drawn into a save in the fifth minute when Alexander headed towards goal.
He made a further stop five minutes later as Billy Clarke's low drive was tipped away from harm's way.
Scunthorpe's first real opportunity of the game came on 14 minutes when Ribeiro drove forward and played in Grella down the right side of the box, whose low strike across goal was easily saved.
Then, a minute later, Barcham got to the left byline and laid the ball back for Ribeiro with a deep cross. However, the Welshman's volley cleared the crossbar with the aid of a deflection.
With 22 minutes on the clock, Slocombe was forced into another save - this time tipping a Nicky Adams free-kick over the crossbar.
After a neat passiing move involving Duffy and Ribeiro, Ryan then cleared the crossbar with a cross-cum-shot.
The hosts went ahead in the 36th minute when Adams' left-wing free-kick was sent into the box and subsequently converted home at close range by the home captain Alexander.
Three minutes before half-time Scunthorpe were presented with a great chance as Walker ghosted his way into the box but Claude Davis managed to get in the way of his drag back for Grant and cleared away to safety.
There was then an even better chance on 44 minutes as Walker's corner reached Mirfin at the back post, who volleyed just wide of goal.
Then, in first half stoppage time, Ryan's cross from the right found Grant in space but the Liverpudlian, trying to unselfish, dragged the ball back across goal, but nobody was there.
It was an even start to the second half, which culminated in Grant smacking the post with a volleyed effort after Grella's flick on ten minutes in, but he was adjudged to be offside.
20 minutes into the second half, the hosts were handed the chance to double their lead. Newey was penalised for a foul in the area on Alexander.
Alexander stepped up and slotted home, sending Slocombe (diving to his right) the wrong way.
Unlike Tuesday night's fightback at Derby, chances were few and far between in the second half for Scunthorpe, and next to come close was Hoke Akpan who cut inside before curling over for the hosts.
It was the home team who continued to have the better chances, and the next one came the way of Kyle McFadzean, whose header from Adams' corner just cleared the post.
The best Iron chance of the second half arrived ten minutes from time when Barcham laid the ball out wide for Ribeiro, whose right-wing cross was fired wide by Grant.
Shortly after, United made their first change as Jennings came on for Barcham.
The hosts weren't finished from a scoring point of view, and netted again moments later when substitute Forte latched on to a long ball to nod past the advancing Slocombe.
The away side pressed for a consolation but couldn't find it, as Grant had an effort blocked on the line and Grant fired wide, and Crawley saw the game out.
Indeed, towards the end, Scunthorpe had further salt rubbed into their wounds as Duffy was sent off for a second bookable offence.
There was one last chance before the end, as Grant headed wide from a left-wing Grella cross.
Scunthorpe are next in action on Tuesday night when they host Crewe Alexandra.
Attendance: 3,172 (521 away).