Two goals in four first-half minutes put the Mariners well on top and although Cambridge tried to pull things round after the break they left huge gaps at the back and new boy Martin Gritton scored his first goal for the club in the final minute with a lovely chip.
After starting well Grimsby might have had a couple of goals but they let Cambridge back into the game. However, the visitors lacked the firepower to test Anthony Williams in the Mariners goal.
And then the match was effectively decided in four minutes after the half-hour mark.
Grimsby went ahead on 34 minutes when Gritton headed on and leading scorer Thomas Pinault shot in off the post for his sixth goal of the season.
This was a body blow for Cambridge and worse was to follow three minutes later when a sweeping move was finished off by Ronnie Bull with a crisp shot into the bottom corner.
U's striker Jermaine Easter finally tested Williams at the end of the first half but the keeper was able to turn the shot away for the corner.
After Cambridge had pushed forward for much of the second half, Darren Mansaram wasted a great chance for Town when it was three against one following a Cambridge free-kick that left the visitors exposed.
But the miss did not matter and when Gritton was played through right at the end the former Torquay striker finished in some style to give the scoreline a good look far as Grimsby was concerned.
Grimsby are next in action at home to Northampton Town on Tuesday January 11th while Cambridge's new boss Steve Thompson, as if he did not know it, faces a major task if he is to keep the club in the Football League.