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Paul Hayes cracked home a superb right-foot volley to give Scunthorpe a 12th minute lead and then six minutes later MacLean was on hand to finish off from close range, following a cross by Peter Beagrie.
Cambridge were rarely able to find any gaps in a strong home defence, although Luke Guttridge might have done better when an opportunity presented itself.
Stev Angus spared Cambridge further damage when he cleared off the line from Richard Kell and keeper Shaun Marshall pushed away successive attempts by Hayes and Beagrie.
However, Scunthorpe strengthened their lead when MacLean snapped up a rebound off the woodwork in the 71st minute.
Scunthorpe remained well in control and steadier finishing might have brought further rewards as twice MacLean went close as did substitute Ian Kilford, before MacLean headed home his 17th goal of the season in injury time.