A goal from Ollie Banks and two from Gary Roberts, including a penalty, sealed the points for Chesterfield and although Oxford threatened in the second half, the dismissals of Tom Newey and Michael Raynes ended their hopes.
Dave Hunt brought a stunning save from home goalkeeper Tommy Lee with a second-minute volley, but the right-back was badly at fault six minutes later when he failed to clear a right-wing cross and Banks swept the ball in at the back post.
Chesterfield scored again in the 16th minute when Ian Evatt was pushed over by Johnny Mullins and Roberts fired the penalty into the top corner to put the home side firmly in control.
Oxford had a chance to change that in the 59th minute when Ryan Williams went clear, but Lee made another crucial save and he then denied Mullins from close range three minutes later.
The visitors fell apart in the last 10 minutes when Newey was red-carded for a late lunge on Ollie Banks.
Raynes was shown a second yellow card for a trip on Roberts and Mullins was stretchered off in stoppage time before Roberts scored a second against eight men.