The league leaders went ahead early on through Shaun Miller, and second half strikes from Dave Kitson and Nick Blackman extended the lead to hand Danny Wilson's side all three points.
The Iron went into the match making no changes from the side that won 3-1 at Leyton Orient a week-and-a-half earlier.
Steve Mildenhall started in goal, with Christian Ribeiro, Paul Reid, Niall Canavan and Tom Newey forming the defence.
The midfield consisted of Mark Duffy, Michael Collins, Damien Mozika, Jimmy Ryan and Andy Barcham, with Karl Hawley leading the attack.
The substitutes were Sam Slocombe, Callum Kennedy, Robbie Gibbons, Nathan Ellington, Matt Godden, Mike Grella and Adda Djeziri.
The Iron got off to a bright start at a rainswept Bramall Lane, but didn't create anything of note before the Blades went ahead through Shaun Miller on five minutes.
He received the ball on the left before cutting inside and firing a low effort beyond the dive of Mildenhall.
After the goal, the hosts tried to extend their advantage but nothing came of a couple of corners.
Then, the Iron won a couple of their own, but the Blades did well to clear away the danger.
Mildenhall was drawn into a save in the 16th minute as the hosts broke on the counter-attack following the breakdown of an Iron forward move. However, despite having plenty of time, Nick Blackman drew a stop from the Iron custodian.
Three minutes later, a left-wing cross from Miller flashed across the Iron box but, luckily for Scunthorpe, nobody got on the end of it.
On 24 minutes, the Iron came close as Duffy's crossfield ball found Barcham, who crossed but Mozika was only just unable to connect.
Scunthorpe were very nearly level on 33 minutes when Ryan's right-wing cross found Mozika, whose angled headed cannoned back into play off the post. Barcham then tried saw his rebound shot saved by George Long.
The Iron won a free-kick on the edge of the Blades' box on 40 minutes but Duffy's deflected effort on the turn drew a fairly routine stop from Long.
On the stroke of half-time, Duffy then delivered an excellent right-wing cross which narrowly evaded three Iron players desperately trying to get on the end of the ball.
Home substitute John Cofie almost had an instant impact as he very nearly forced a mistake from Mildenhall when he had the ball at his feet. However, he quickly recovered the situation and cleared.
The hosts did make it two on 59 minutes though when Kitson connected with a right-wing free-kick to guide a header past Mildenhall.
With second half chances few and far between for both sides, the visiting side made an alteration on 65 minutes when Ryan was replaced by Ellington.
Two minutes later, after he had played his way into space with some decent trickery down the right, Blackman's prod towards goal drew a decent stop from Mildenhall at his near post.
Then, on the counter-attack, there was a rare Iron second half shot at goal, as Duffy struck a shot wide after a solo run.
A second Scunthorpe change was made twelve minutes from time when Djeziri came on for Hawley.
The Blades were awarded a penalty with six minutes remaining as Newey upended Ryan Flynn following a sweeping move down the right hand side of the Scunthorpe area.
Blackman then stepped up to slot home, sending Mildenhall diving the wrong way.
There was one final Iron change during the four minutes of stoppage time as Kennedy came on for Duffy.
It proved the last notable action of the afternoon, with Scunthorpe returning to action on Saturday when they visit Tranmere Rovers.
Sheffield United: Long, Maguire, Hill, Flynn, Doyle, Blackman, McDonald, Miller (Cofie, 45), Kitson (Cresswell, 87), Collins (Williams, 53), McMahon.
Substitutes not used: Westlake, McAllister, Ironside, Coyne.
Scunthorpe United: Mildenhall, Ribeiro, Reid, Canavan, Newey, Duffy (Kennedy, 90), Collins, Mozika, Ryan (Ellington, 65), Barcham, Hawley (Djeziri, 78).
Substitutes not used: Slocombe, Gibbons, Godden, Grella.
Referee: Gary Sutton.
Attendance: 21,819 (663 away).