At a time when the Saints sit at the bottom of the Premier League standings, Grimsby are in 16th spot in League Two and will be sensing another upset in this competition.
Match preview
On the back of such an eye-catching win at Chelsea, Southampton's supporters expected their side to replicate that performance when they travelled to Leeds United last weekend.
Instead, the Saints delivered a display which was more in keeping with Nathan Jones's reign as their relegation rivals prevailed by a 1-0 scoreline at Elland Road.
As a result, Selles's side are now four points adrift of safety, yet the Spaniard will view this fixture as a welcome distraction as he bids to build some confidence within his squad.
Despite the understandable frustration at St Mary's, however, Southampton have won five of their most recent 11 matches in all competitions.
In the FA Cup, 2-1 victories have been posted against Crystal Palace and Blackpool respectively, and Selles will demand that a wider success is posted on Wednesday night.
Nevertheless, Southampton can ill-afford any complacency against opponents who thrashed Championship side Luton Town in a fourth-round replay.
While the Hatters made changes for that fixture, few expected the Mariners to prevail by a 3-0 scoreline, and Paul Hurst will be relishing the opportunity to move Grimsby into the quarter-finals of this competition for the first time since 1939.
Although Grimsby have little to play for in League Two, Southampton will take note of their recent showings in the fourth tier, the latest earning them a 2-2 draw with leaders Leyton Orient.
Five points have been collected from their last three matches, and Grimsby have seven wins from 15 games on the road in the league this campaign.
Southampton FA Cup form:
W
W
Southampton form (all competitions):
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L
L
L
W
L
Grimsby Town FA Cup form:
W
W
W
D
W
Grimsby Town form (all competitions):
W
L
L
W
D
D
Team News
Selles is expected to make numerous changes to his Southampton XI with Kyle Walker-Peters and Theo Walcott among those in line for recalls.
Ibrahima Diallo and Sekou Mara will also expect to start, while goalkeeper Willy Caballero may be given a run out between the sticks.
Che Adams will hope to return from a knock, but this game will come too soon for Mislav Orsic who is still recovering from concussion.
With George Lloyd having already represented Cheltenham Town in this year's competition, Hurst will have to make one change to his Grimsby side.
Danilo Orsi, who scored in the previous round, could return down the middle of the attack, but the remainder of the team may stay the same.
Southampton possible starting lineup:
Caballero; Walker-Peters, Caleta-Car, Salisu, Perraud; Walcott, Ward-Prowse, Diallo, Elyounoussi; Sulemana, Mara
Grimsby Town possible starting lineup:
Crocombe; Efete, Waterfall, Maher; Emmanuel, Holohan, Hunt, Driscoll-Glennon; Clifton, McAtee; Orsi
We say: Southampton 2-0 Grimsby Town
With Southampton likely to make alterations, Grimsby will be optimistic about taking full advantage. However, for all their struggles, the Saints still possess a talented squad, and they should have enough quality to make relatively light work of their next opponents.