The Reds' first 3pm kick off of the campaign comes at the end of a significant week for Jurgen Klopp's side.
Victories away at Spurs and at home to Paris Saint-Germain have done little to stem the flow of optimism on Merseyside, and with six wins from six in all competitions Klopp's men will be confident of extending their run against a Saints side still finding their feet under Mark Hughes.
Liverpool's links with Southampton, in the transfer market at least, are well known.
Here, Goal takes a look at everything you need to know ahead of Saturday's meeting...
Liverpool were handed a boost with the return to training of Dejan Lovren this week. The former Southampton man has not played a competitive game since the World Cup final due to an abdominal problem, but is ready to bolster Klopp's numbers during an intense run of fixtures.
Roberto Firmino was Liverpool's match-winner against PSG despite an eye injury, and should be able to start this game if needed. Adam Lallana, another ex-Saint, is still sidelined with a hamstring issue.
Alex Oxlade-Chamberlain and Rhian Brewster are long-term absentees.
Liverpool do not have any suspended players for this game.
Likely Liverpool starting line-up
Klopp has still only used 13 different players from the start this season, with Daniel Sturridge becoming the 13th on Tuesday night.
We can expect a couple of changes against Southampton. Naby Keita, who didn't feature against PSG, should start while it would be a surprise if Firmino was not recalled too.
Fabinho? He made his belated debut as a last-gasp substitute in midweek, could he be called on from the start against Saints?
Southampton team news
Danny Ings cannot play in this game as he is on loan from Liverpool.
Other than that, Hughes has a full squad to choose from, though may look to make changes given the way his side threw away two points against Brighton on Monday night.
TV channel & kick-off time
The fixture will not be broadcast live on UK TV this weekend, due to its 3pm kick off time. Fans can catch highlights on Sky Sports Premier League, or on BBC One's Match of the Day, from 10.30pm.
In the United States the game can be watched live on television on NBC Sports, kick off 10am ET.
Best Opta match facts
Southampton have won just three of their 19 Premier League visits to Anfield (W3 D6 L10), their last victory coming in September 2013.
Liverpool have kept a clean sheet in each of their last four Premier League games against Southampton – the Reds’ longest current run in the competition.
Liverpool are looking to start to top-flight campaign with six consecutive wins for the third time in their history, after 1978-79 (finished 1st) and 1990-91 (finished 2nd).
Liverpool are unbeaten in their last 23 Premier League games at Anfield (W15 D8), their best run in the competition since August 2009 (31 games).
Liverpool have kept a clean sheet in each of their last seven Premier League home games; only twice have they had a better run in the competition (9 in February 2007 and 8 in January 2006).
Since the start of last season, Southampton have dropped more points from winning positions than any other current Premier League side (26).
Liverpool’s Sadio Mané has scored 48 Premier League goals and could become the seventh African player to reach 50 in the competition (Efan Ekoku, Yakubu, Kanu, Didier Drogba, Emmanuel Adebayor and Yaya Touré).
Danny Ings has netted three goals in his five Premier League games for Southampton, the same number he scored in 14 matches across his three seasons with Liverpool in the competition.
Mohamed Salah was directly involved in four of Liverpool’s five Premier League goals against Southampton last season, netting twice at Anfield and both scoring and assisting at St Mary’s.
This will be Liverpool manager Jurgen Klopp’s 600th league game in charge in his career – his current record is P599 W295 D158 L146.