The Citizens are eight points adrift of leaders Liverpool with a game in hand, while Southampton are four points better off in third after a superb start to the campaign.
City seemed happy to accept a point from their recent derby clash with Manchester United, but there was little to celebrate following Tuesday's 1-1 draw with West Bromwich Albion.
Guardiola accepted after the game that his side cannot afford to drop points against sides such as West Brom, who still went ahead and sacked boss Slaven Bilic after the match.
City have won back-to-back league games just once all season and are already playing catch up on Liverpool with two thirds of the season to go.
This trip to St Mary's is not exactly the easiest of matches on the face of it, either, with Southampton in great form at the moment.
That came on the back of successive wins over Brighton & Hove Albion and Sheffield United, the Saints having now lost only one of their last 11 league matches.
They won this corresponding fixture 1-0 last season, too, thanks to Che Adams's strike - his first for the club - when the sides last faced off in July.
That ended a six-match losing run against City and Southampton will feel, on recent form, that they may well be the favourites to win this game and keep their outside title hopes alive.
Southampton Premier League form: WDLWWD
Manchester City Premier League form: DLWWDD
Manchester City form (all competitions): WDWWDD
Hasenhuttl has no injury or suspension concerns for Saturday's match and may well stick with the same XI that started against Arsenal.
Danny Ings has gone back-to-back games without scoring, though he still has six goals and three assists in 10 league outings this term.
Sergio Aguero is slowly regaining his fitness but, with City in need of goals, the Argentina international is expected to be handed only his third league start of 2020-21.
Southampton possible starting lineup:
McCarthy; Walker-Peters, Bednarek, Vestergaard, Bertrand; Walcott, Ward-Prowse, Romeu, Armstrong; Adams, Ings
Manchester City possible starting lineup:
Ederson; Walker, Stones, Dias, Cancelo; Fernandinho, Gundogan; Mahrez, De Bruyne, Sterling; Aguero
We say: Southampton 1-1 Manchester City
Southampton have won four of their last five league matches, keeping a clean sheet in each of those victories.
City have been far too inconsistent this campaign, as highlighted in their 1-1 draw with West Brom, and we can see this being another frustrating afternoon for Guardiola's men.
Top betting tip
Watch the Sports Mole Football Shorts prediction for this game below: