Alan Buckley's men had been presented with the first goal on just five minutes when Macclesfield's centre-backs, Sean Hessey and Ryan Cresswell, looked at each other as Danny North hurtled through the gap before lobbing the advancing Jonathan Brain from 20 yards for his ninth goal of the season.
Mariners' keeeper Phil Barnes then kept young striker Gareth Evans at bay with two athletic saves to stop powerful shots from the edge of the box.
Brain also had to be on top form to thwart a close-range Peter Till header.
After the break Grimsby should have gone further ahead as North sprung the offside trap only to fire wide from ten yards.
Macclesfield then started to come back into the game and should have equalised on 70 minutes when on-loan striker Michael Symes headed over the bar from six yards.
They finally got their just desserts when Evans blasted home a volley from ten yards as he latched on to a weak clearance from Nick Fenton.
However, the home defence stood still to allow Clarke to bury the winner just three minutes later.
In four minutes of injury time Macclesfield had two golden chances to equalise but first Jamie Tolley's 15-yard shot struck Barnes on his outstretched legs before skipper Terry Dunfield fired wide from the edge of the box.
After the game Alan Buckley said: "I am delighted with the result. It was an excellent first-half performance and, though we were presented with the first goal, I felt we could have gone further ahead during that half. After the break we fell away and I felt their goal was coming but we responded as we've done all season, keeping our heads high."