Grimsby forced the early pace in the game through Jean-Paul Kalala and striker Adam Proudlock.
Kalala raced through the middle after only three minutes before firing narrowly wide and then, two minutes later, Proudlock, signed from Darlington earlier in the season, fired a dipping volley narrowly over from 25 yards.
The hosts began to pressurise and Phil Barnes' goal came under threat in the 13th minute when Liam Hatch couldn't apply the finish at the far post after the Grimsby defence had failed to clear a Franz Burgmeier corner.
Burgmeier went close to opening the scoring when he fired against a post after Barnes had done well to parry a shot from Ricky Ravenhill in the 24th minute. Jason Kennedy then fired against the crossbar from close range in the 36th minute as the Grimsby goal again came under pressure.
Proudlock, who proved to be a handful to his former employers all afternoon, had a further chance four minutes before the interval. Proudlock connected with a low cross from Adrian Forbes, but sent his low volley from inside the area wide of the Darlington goal.
Darlington had a couple of early chances in the second half through Burgmeier in the 50th minute and Kennedy eight minutes later.
Kennedy the better of the two chances as he fired wide from ten yards after Danny Carlton had flicked on a Rob Purdie cross.
In the 73rd minute Darlington captain Steve Foster headed a Burgmeier free-kick over the bar from inside the six-yard box.
Carlton somehow missed the best chance of the game ten minutes from time when he fired wide of the target from six yards out and with goalkeeper Barnes out of position.
Darlington continued to press and, three minutes from time, Main rose to head in a Ravenhill cross to seal victory.