The injured midfield duo of Grant McCann and Sam Togwell were replaced by Matt Sparrow and Krystian Pearce, with Andrew Wright partnering Sparrow in the middle of the park.
United were poor in the first half but had the better of the chances. Thompson and Sparrow both went close and Rotherham's Reid couldn't beat Murphy from close range.
Sparrow picked up an unnecessary yellow card moments later, lunging into a challenge with Rotherham keeper Warrington- the visiting fans calling for a red card, but referee Clive Oliver showed a yellow after consulting his linesman.
Martyn Woolford drove United on in the second half and started the move which led to a simple finish. He ran at the Rotherham backline before laying the ball into Hooper for a one-two and sidefooted past Warrington to clinch the opening strike.
Woolford then had a chance to put the game to bed as the ball was cut back by Sparrow, but Warrington pulled off a fantastic save to deny United's star man.
However it was the former York man who set up the next goal from the resulting corner, with Krystian Pearce rising above the Rotherham defenders to power a header over the 'keeper.
Scunthorpe dominated from then on and their league two visitors couldn't cope with the pacy play. Hooper had chance to make it three, but curled a superb effort just wide after Sparrow's backheel played him in.