Defender Chris Doig had fired the Cobblers into a 17th-minute lead; but Colin Calderwood's men took complete control when Martin Smith and Josh Low struck in quick succession.
Smith collected a pass from Scott McGleish and finished with a superb low drive from the left side of the penalty area for his second goal in successive games. Oxford's defence had not recovered fully from that when goalkeeper Billy Turley was hesitant in dealing with a bouncing ball from Jason Lee's cross, and Low arrived at the far post to head in just under the bar.
Oxford pulled a goal back four minutes later when former Northampton defender Chris Willmott powerfully headed home Andy Burgess' free-kick. But they finished well beaten, and still face a massive fight to stay in the Football League especially as they must play promotion-chasing Leyton Orient on the final day.
Doig's third goal of the season had put Northampton on their way and he completed the set by doing so. After having previously scored with his head and right foot this season, he added a sweet left-foot shot to his collection. None of the Oxford defence attacked David Hunt's left-wing corner, and Doig fired into the net on the turn.
Calderwood's team always looked the more accomplished, with a better touch on the ball, and a defence that has the best goals-against record in League Two.
Turley had to come quickly off his line to save from Low inside the first 40 seconds, and the Oxford keeper also made a spectacular one-handed save to turn Lee's flicked header over the bar.
Cheered on noisily by a 2,500-strong support in this local derby, Northampton always created the more clear-cut chances, and Sean Dyche wasn't far away with a left-foot snapshot over the bar.
Oxford boss Jim Smith brought on strikers Steve Basham and Yemi Odubade in the second half in a bid to get back in the match, but this was Northampton's day. Substitute Andy Kirk almost got a fourth in injury time, but blazed over from 15 yards.