Rampant Vale were straight into top gear with Tom Pope going close before Louis Dodds fired the home side into an eighth-minute lead.
Pope nodded the ball into his path and Dodds took a touch before blasting a left-footed shot past an unsighted Adam Collin from 16 yards.
Rotherham should have levelled in the 18th minute when Sam Johnson saved Kieran Agard's penalty low to the keeper's right after James Tavernier had been tripped by Richard Duffy.
Michael O'Connor also struck Johnson's right-hand post with a 25-yard free-kick right at the end of a full-blooded and entertaining first half.
But the contest swung Vale's way eight minutes after the interval when Rotherham centre-back Claude Davis was sent off for kicking Pope as the striker lay on the floor.
Pope then climbed to his feet to lay on the killer goal as Gavin Tomlin fired a low right-footed shot past the on-rushing Collin from 12 yards in the 68th minute.