Grimsby fought back from two goals down before a late Danny Andrews free-kick gave Macclesfield all three points in a thrilling encounter.
Scott Boden turned in Jack Mackreth's cross early on and Chris Holroyd then made it 2-0 from close range.
Silkmen defender Steve Williams diverted the ball into his own net and Chris Doig's header levelled it.
Holroyd had a penalty saved by Mariners keeper James McKeown after he had been fouled before Andrews settled it.
VIEW FROM THE DRESSING ROOM
Grimsby Town manager Paul Hurst told BBC Radio Humberside:
"Obviously we're disappointed to lose any game - and to lose at home and lose the unbeaten run.
"What I would say is I've not got a good feeling at this present time. The dressing room was extremely quiet but it's a long time since we had that feeling.
"Overall, I'm disappointed but I'm not going to be too harsh on the players because of all the hard work we've put in and they've particularly put in to go on this run of games. That doesn't go out the window because of one defeat.
"I think they showed they're a decent team and kept the ball well. I'm frustrated for that closing period but we couldn't get a head of steam up to get the equaliser."
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