The trip to St Mary’s comes just 64 hours after the Reds lifted another European trophy in Istanbul, meaning recovery and preparation time has been far from ideal.
This could result in Klopp making several changes to his starting team at St Mary’s, to keep things fresh after a draining 120-minutes in Turkey.
So who could come into the team and how could Liverpool’s starting XI look for the first away league fixture of the season?
Liverpool’s injury luck goes from bad to worse, as Super Cup exploits have come at a cost with two more injuries picked up.
Now joining the No.1 on the side-lines is Naby Keita, who is ruled out of Saturday’s match with a muscle injury sustained in final preparations.
In addition, and somewhat incredibly, Klopp revealed Adrian is a doubt due to an ankle injury sustained when a pitch invader collided with the Istanbul hero during post-shootout celebrations.
The Squad & Fresh Legs
Klopp’s rotation will be made extra difficult and could yet see changes made in every area – including in goal.
Options are just about available in the rest of the team to give the lineup some energy, if not totally fresh legs.
One man certain to return is Roberto Firmino, who will be back to spearhead the attack after transforming Liverpool’s performance in midweek.
Liverpool’s XI vs. The Saints
Subtle switches seem more likely than wholesale changes, re-introducing players who featured as substitutes against Chelsea to retain rhythm and continuity in performance.
Alexander-Arnold – on for only extra time on Wednesday – should come in for Gomez who has played every minute of the first three games after a long-term absence.
Wijnaldum played an hour after coming on for Milner, meaning the Dutchman should be ready to start in place of the vice-captain.
And Firmino, who has looked incredibly sharp despite barely any rest this summer, showed he is more than ready to re-form the famous front three.
There is going to have to be greater rotation this season as the Reds carry an even smaller squad for a campaign with more games.
It’s not often that it comes just two league games into a new season, but it may have to after a long night in Istanbul and in order to keep performance level at the highest.
And we could see changes made in all areas.
If Adrian’s recovery doesn’t go to plan, Lonergan would start with his experience preferred to Kelleher’s youth.
The same back-four as above should line up to protect Gomez, but the midfield could boast a very different look.
Both Fabinho and Henderson played the full 120 minutes in Istanbul, so taking one out makes sense to retain energy in midfield.
Withdrawing Fabinho – who was visibly shattered at the final whistle – would allow Wijnaldum to step into the No.6 role, leaving Henderson in his pressing position.
To complete the central unit could be Lallana, who will be fresh and ready to make an impact which he showed he can do with a bright cameo outing in the Community Shield.
Mane played over 100 minutes on his first start of the season in Turkey, so managing the Senegalese would also be wise.
Origi can slot back in on the left, joining Firmino and Salah in what would be a much-changed Liverpool side boasting six changes.
Whether Klopp ultimately opts for a more regular-looking lineup or an experimental side at St Mary’s, three points is required to keep building a fast start.