Jon Otsemobor is out with the calf strain sustained in the midweek Carling Cup defeat to Blackburn Rovers.
But Owls captain Rob Jones returned after missing the last two games with a broken nose.
Gary Madine put Wednesday in front after five minutes, but then there was a penalty scare in front of the Kop.
David Prutton was judged to have fouled a Scunthorpe player in the box, but clearly played the ball. Referee James Linington pointed to the spot, but after much protest he consulted his linesman and changed his decision.
Clinton Morrison was then on his own goal-line to clear a goal-bound shot as Iron pushed for an equaliser.
But it was the hosts who got the second, on-loan Ben Marshall racing down the left before firing a shot beyond Josh Lillis in the Iron goal.
Chris Dagnall struck the post as Scunthorpe looked threatening in attack and they pulled a goal back in the 67th minute, Bobby Grant rolling his effort beyond Nicky Weaver.
Three minutes later and the two-goal cushion was restored as Madine raced away and fired inside the far post.
Still Scunthorpe played their football and Mark Duffy scored their second goal of the afternoon with five minutes remaining.
“That’s a terrific win,” said Owls boss Gray Megson.
“That wasn’t the best we have played at home this season by any means but we have stuck in there, scored three goals and I thought we were good value for the win.
“Scunthorpe did well and never gave in. Some of our defending was not what you would expect and we will have to look at what we are doing there in training and go back to where we were in pre-season training.”
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