In the second of three matches between the two sides in seven days the Mariners took the spoils with a confident display despite making five changes to the midweek starting line-up.
Among those given a chance to shine was striker Peter Bore, who was handed his first start of the season up front with Gary Jones.
And Bore took his opportunity with both hands as he scored two first-half goals to give Grimsby a winning platform.
Bore's first came on 21 minutes when a David Artell clearance rebounded neatly into his path and he drilled home a low right-foot shot past Scott Davies' right hand.
Three minutes later Bore made it 2-0. A Jim Bentley clearance fell for Jones and although his shot was parried by Davies, the youngster was on hand to head home from close range.
A shocked Morecambe came back strongly with Garry Thompson hitting the woodwork with a left-footed shot that beat Gary Montgomery, but came back off the inside of the post and bounced to safety.
Morecambe began the second half on top with Thompson shooting wide and Grimsby defender Julian Whittle producing a superb covering tackle to block Matty Blinkhorn's goalbound shot on 50 minutes.
Montgomery then produced a fine reflex save to fist away a well-struck Blinkhorn shot on the turn as the Shrimps looked to get back in the game.
But Morecambe's hopes of a comeback were dented as Grimsby extended their lead on the hour.
Paul Bolland saw a shot from the edge of the area hit a post and although Bore's follow-up was well blocked by Davies, wing-back Nick Hegarty was perfectly placed to hammer home the loose ball from close range.
The visitors then added insult to injury with a fourth goal ten minutes from time as substitute Martin Butler scored with his first touch of the ball as he turned in Nick Fenton's downward header from close range.
The Shrimps were denied a late consolation as Henry McStay and Garry Hunter fired wide as Grimsby recorded an excellent win.