Dominic Samuel and Gavin Massey both went close for Colchester early on, while Scunthorpe debutant Akpo Sodje fired straight at keeper Mark Cousins and the U's keeper then denied both Jimmy Ryan and Andy Barcham.
Ryan cleared Josh Thompson's close-range effort off the line, and four minutes before the break Ryan's blistering 25-yard strike flew into the net, despite Cousins getting a hand to the shot.
Scunthorpe doubled their lead in the opening minute of the second half when Karl Hawley finished well from close range from Sodje's flick-on.
It was almost 3-0 soon after when Callum Kennedy's free-kick rattled the woodwork and Hawley did the same, before Colchester substitute Freddie Sears reduced the deficit when he lashed home from close range after latching onto Clinton Morrison's flick.
Colchester pressed for an equaliser in the closing stages but were unable to prevent a club record ninth successive league defeat.