Terry Hawkridge got the solitary goal for the Iron either side of the visitors' strikes.
The away side took the lead early in the first half, when John-Lewis put Grimsby ahead with an accurate finish past Sam Slocombe.
An equaliser from Hawkridge looked to put the Iron back in the game, before McDonald put the Mariners back in front with a powerful header from a Scott Kerr free-kick.
The Iron made four changes from the side that lost 2-0 to Accrington Stanley at Glanford Park; with Ribeiro coming in for Byrne, Hawkridge replacing the cup-tied David Syers, Mirfin returning in place of Luke Waterfall, whilst Jimmy Spencer took the place of Etienne Esajas in the starting XI.
Grimsby, meanwhile, remained unchanged from both the first game against Scunthorpe and their Skrill Premier fixture against Tamworth, which they won 2-0.
The visitors began proceedings to the replay, however it was Scunthorpe who were the first to get at the defence and carve out an opportunity. Winnall made several bursts into the box in the first few minutes. Hawkridge nearly got the Iron off to a great start, his drilled cross was well blocked and then cleared by the Grimsby defence.
In what was an end to end start to the game, Grimsby managed to get an early goal to put the Mariners 1-0 up. Colbeck’s volley struck the top of the post before Lenell John-Lewis finished low and hard into the far corner beyond Slocombe, after finding himself in space within the box.
The atmosphere was rocking at Glanford Park, with both sets of supporters making plenty of noise. The Iron refused to sit back despite the early setback. With a free-kick on the left, Hawkridge put whipped a cross into the box, both sets of players failed to get a head on the ball, with Mirfin lurking at the back post. However, he failed to make his position count as the ball sailed out for a goal kick.
Scunthorpe took confidence from that chance and came so close to getting the equaliser on 21 minutes. Sam Winnall picked up the ball on the edge of the box with space to shoot. He got his shot away before being blocked by a Grimsby defender. The deflection nearly took the ball past keeper James McKeown, however the Mariner number one made a great save to keep his side one up.
As the game went on and drawing onto half time, neither side managed to get any attempts on goal, with both defences looking strong at back and stopping any sort of opening in the boxes. Scunthorpe began to knock on the door towards the end of the first half, but failed to get a chance on goal, leaving both sides going into the break with Grimsby leading 1-0.
After the break, Scunthorpe couldn’t have asked for a better start. Good play down the left side between Dawson and Winnall saw Winnall whip a dangerous cross into the box. There were claims for a penalty with Burton believing he was fouled. However, the ball found its way to Hawkridge, who bundled the ball goal wards. McKeown could only watch as it trickled its way past him and into the back of the net.
After the goal, Scunthorpe looked to build on their fast paced start to the second half. The Iron were awarded a free-kick on the edge of the box. Dawson and Hawkridge stood over the set piece but it was Dawson to take it. It was heading for the top corner, however the Grimsby keeper made a fantastic save to deny the hosts from taking the lead.
It wasn’t long until Grimsby went back ahead however. A free-kick was whipped in following a foul by the goalscorer Hawkridge. In amongst a crowded box, it was Clayton McDonald to rise highest from Scott Kerr’s cross and head the ball beyond Slocombe into the far corner of the net to make it 2-1.
The game continued to be end to end with Spencer the next player to have a chance at goal this second half. He won the ball well outside the area before creating space for himself and getting a shot on goal. The keeper got his body behind the ball but failed to clutch onto the powerful shot. There wasn’t any Scunthorpe players nearby to claim the rebound as McKeown claimed the ball on his second attempt.
The introduction of Adelakun nearly brought an equaliser almost instantly. The substitute found himself in acres of space on left hand side as he put the ball into the box. Burton couldn’t control the ball but it made its way to Winnall. He managed to scramble a shot away, however it wasn’t powerful enough to find a way past McKeown as he saves comfortably.
Scunthorpe continued to press Grimsby and a counter attack nearly gave them that equaliser. Winnall received the ball in the centre circle before driving at the Grimsby defence. Hawkridge, in support on his right, then got the ball and put in a dangerous cross but it was defended well by the defenders.
The Iron continued to try and break down the Grimsby defence, pumping balls into the box and trying to get round the back four, however the Mariners stayed strong at the back and didn’t allow the Iron a clear opportunity to get the goal to take it to extra time. The visitors saw the game out and claimed the 2-1 win. The victory for Grimsby was their first win against the Iron in five games in all competitions.
Scunthorpe United: Slocombe, Ribeiro, Mirfin, Canavan, Dawson, Hawkridge, Collins, McAllister, Winnall, Burton (Iwelumo 78), Spencer (Adelakun 70).
Substitutes not used: Severn, Esajas, Waterfall, Hornsey, Byrne.
Grimsby Town: McKeown, Hatton, Thomas, Kerr, Pearson, Colbeck, Disley, Neilson (McLaughlin 73), McDonald, John-Lewis, Hannah (Rodman 88).
Substitutes not used: Hedge, Doig, Cook, Hearn, Bignot.
Attendance: 5,699 (1,984 away).