Grimsby ended Cambridge's perfect home record in the Conference Premier and prevented the U's moving level on points with leaders Luton Town.
Richard Money's side, who had won all 12 of their previous league outings at the Abbey Stadium, fell behind to a first-half goal from Lenell John-Lewis.
His close-range effort was cancelled out when Luke Berry headed in an Ashley Chambers cross on 54 minutes.
Scott Neilson's deflected shot through a crowded area won it for Grimsby.
Luton remain three points clear of Cambridge at the top of the table, while the Mariners have consolidated their play-off position and are now up to fourth.
VIEW FROM THE DRESSING ROOM
Grimsby Town boss Paul Hurst told BBC Radio Humberside:
"The last thing [I said] going out was 'are we good enough to come and get three points?' - I wrote that on the board and asked the lads the question.
"I said I believed in them, that they were good enough, but ultimately it's about going out on the pitch and proving that.
"I thought it was a deserved win, Cambridge are a good side, it's a fantastic record they have had - law of averages, they're going to lose one eventually, and I'm delighted it is us that has put an end to that run.
"I've said all along, I think we are capable of going anywhere and winning."
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