But Oxford fans were cursing the rashness of a tackle from winger Chris Hackett in the 58th minute just when the U's had battled back from conceding an early goal, and looked set to go on and win.
Referee Grant Hegley immediately produced the red card for Hackett's two-footed lunge on Andy Parkinson.
With ten men for the final half hour, the U's were always going to be up against it and Paul Bolland punished them with a stunning right-footed shot into the top corner from 20 yards out.
Gary Cohen extended Grimsby's lead to 3-1 in the final minute when he got to the ball ahead of Oxford keeper Billy Turley to stab home a close-range shot.
Incredibly, there was still time for the home side to pull another goal back from the penalty spot, through substitute Steve Basham, after Justin Whittle fouled fellow sub Neville Roach although the challenge looked to be outside the box.
Grimsby had got off to a great start with Parkinson shooting low past Turley from 15 yards after good work by Michael Reddy.
Scott Parkinson levelled on his debut for Oxford six minutes into the second half with a firm shot from the edge of the box. But Eric Sabin missed a golden chance and with Hackett's dismissal, the match swung Grimsby's way.