Arne Slot's men opened up a five-point lead over Manchester City at the summit of the table in gameweek 11, where Darwin Nunez and Mohamed Salah produced the telling contributions in a 2-0 win over Aston Villa.
The reigning champions can cut the deficit down to two points by beating Tottenham Hotspur on Saturday evening, but few will expect Liverpool to leave St Mary's with anything less than a victory to show for their efforts.
Here, Sports Mole rounds up all of Liverpool's latest injury and suspension news ahead of their clash with the Saints, who sit rock bottom of the standings.
Virgil van Dijk
Status: Minor doubt
Type of injury: Unspecified
Possible return date: November 24 (vs. Southampton)
Virgil van Dijk missed the Netherlands' second UEFA Nations League match of November against Bosnia-Herzegovina on medical grounds, but he is not believed to be carrying a serious issue and should be OK to feature at St Mary's.
Trent Alexander-Arnold
Status: Major doubt
Type of injury: Hamstring
Possible return date: November 24 (vs. Southampton)
In contrast, Trent Alexander-Arnold is much more of a doubt due to the hamstring issue he sustained in the win over Villa, although he avoided a serious problem and has not been ruled out just yet.
Diogo Jota
Status: Out
Type of injury: Abdominal
Possible return date: December 7 (vs. Everton)
There was hope that Diogo Jota would return straight after the November hiatus, but Slot has now conceded that the Portugal international may not return from his abdominal concern until the early stages of December.
Alisson Becker
Status: Major doubt
Type of injury: Hamstring
Possible return date: November 24 (vs. Southampton)
Alisson Becker has been seen in full training with the Reds as he steps up his recovery from a hamstring problem, and there is a slim chance that the Brazilian will be back in the Reds' ranks this week.
Federico Chiesa
Status: Major doubt
Type of injury: Fitness
Possible return date: November 24 (vs. Southampton)
Similarly, Federico Chiesa has had a couple of uninterrupted weeks to get back to full speed, having struggled with several niggles since joining from Juventus, but the Italian winger will likely be gradually eased back into action.
Harvey Elliott
Status: Major doubt
Type of injury: Foot
Possible return date: November 24 (vs. Southampton)
Over the international break, foot fracture victim Harvey Elliott was pictured in a full training session with the Reds' Under-21s, so the Englishman is also pushing to make his comeback in the contest with the Saints.
LIVERPOOL'S SUSPENSION LIST
Liverpool have no players suspended for this match.