It will be the ninth occasion that Jurgen Klopp will pit his wits against the Saints; a side he has only previously beaten twice.
Virgil van Dijk, meanwhile, returns to St Mary's for the first time since his £75 million switch to Liverpool.
The centre-back can expect a hostile reception, but he won't be alone in that regard given the Reds' penchant for purchasing from the south-coast club.
Joe Gomez sat out the 2-2 draw with Tottenham last Sunday due to a knee issue and hasn't trained since so will again be absent. "He was running outside but not with the team but that means he's close," he said.
"I don't think he has a chance for Sunday if they don't come in and say the running was the good! We can have him this afternoon as well but then Porto, there's a chance. We will see."
Adam Lallana is closer to match sharpness following a muscle complaint and is in contention to be in the squad, while Ragnar Klavan has trained after a similar problem.
Nathaniel Clyne is closing in on rejoining first-team training following a back operation, but having not played at all this season, will take a while to get into his stride.
Neither side have any suspension concerns for this fixture. Lallana has a three-match ban for non-first team games after being sent off for the Under-23s in their defeat to Tottenham.
LIVERPOOL POTENTIAL STARTING LINE-UP
Liverpool tackle Porto away in the last-16 of the Champions League on Wednesday and Klopp will be mindful of that, but they cannot lose grip in the top-four challenge.
The Reds boss should go strong on Sunday, where the major points of interest will be in defence and midfield.
Does he continue with the Van Dijk and Lovren pairing, or will Joel Matip return to the fold for either of them?
The Netherlands international worked well with the Croatian against Spurs, but the latter hasn't always had the easiest of times against his former club.
In the centre of the park, Gini Wijnaldum and Alex Oxlade-Chamberlain have been named on the bench for the last two fixtures with James Milner starting alongside Jordan Henderson and Emre Can.
Liverpool have lacked dynamism in the middle, which Ox can provide. Lallana is also a more forward-thinking option.
There is the luxury to rotate at left-back if Andy Robertson is to be kept fresh for Porto, with Alberto Moreno ready to fill in.
SOUTHAMPTON TEAM NEWS
Southampton ended their 12-game winless run with victory at West Bromwich Albion last week, and are looking to secure back-to-back wins in the league for the first time since April 2017.
Jack Stephens has eased the departure of Van Dijk, netting three goals in as many matches. His partnership with Wesley Hoedt at the heart of defence has shown signs of promise.
The latter explained: “We are playing with a consistent squad now, so we are not changing it around too much anymore.
“That’s nice, it’s brings up habits and relationships. Everybody knows what to do and that’s good.
“There’s still 12 more finals to go, we’re not out of danger yet. There are still a lot of improvements to be done.”
Charlie Austin is sidelined for the hosts due to a torn hamstring.
TV COVERAGE & KICK-OFF TIME
Kick off is at 16:30 BST (09:30 CST) and the match will be televised live in the UK on Sky Sports Main Event.
BEST OPTA MATCH FACTS
Jurgen Klopp is set to face Southampton for the ninth time as Liverpool manager, his most faced opponent with the club – he has only won two of the previous eight games (D3 L3) and has only lost as many matches against Leicester and Swansea (also three).
Sadio Mane has scored six goals in his last five Premier League appearances at St. Mary’s Stadium.
There has been just one goal scored in the last two meetings between these sides in all competitions at St. Mary’s – in the two before that, there were 12 goals scored.