The Friday night kick-off gave the Mariners a chance to leapfrog above Wycombe Wanderers into top spot and they grabbed it with three well-taken goals to silence an expectant Whaddon Road crowd.
Cheltenham had moved up to seventh place with some promising displays of late, but they had no answer to the pace and clinical finishing of the Grimsby frontmen.
However, in the first 45 minutes it was Cheltenham who dominated possession, although the visitors created the more meaningful chances.
Visiting striker Gary Jones blazed over the crossbar from 15 yards with 11 minutes gone and only four minutes later the breakthrough goal arrived.
Full-back John McDermott sent a seemingly innocuous long ball forward, but midfielder Paul Bolland had made an intelligent run and used his pace to hold off Gavin Caines before drilling a low shot beyond goalkeeper Shane Higgs.
Cheltenham passed and passed with big striker Kayode Odejayi and winger JJ Melligan prominent, but the best chances they could muster were a long-range curling shot by captain Grant McCann and a clever change of direction and shot from full-back Brian Wilson that also drifted wide.
In fact, Grimsby almost doubled their advantage in first-half injury-time when a low shot from Michael Reddy brought a fine save from Higgs.
Cheltenham continued to huff and puff in the second half but the game was virtually put beyond doubt in the 65th minute when Reddy sprinted away from the halfway line and cut inside the box before drilling a low shot in off the near post.
Substitute Gary Cohen sealed the points with an amazing burst of pace to take him clear of the defence and a sharp finish as the clock ticked into injury-time.
The win was Grimsby's fifth on the road this season and leaves them unbeaten away from Blundell Park in seven games.