Pellegrino took over the reins at St Mary's Stadium in the summer having once been a part of Rafael Benítez's first-team squad and backroom staff in two spells at the Merseyside club.
But he makes his way back to Liverpool amidst growing concern that he is unequipped to remedy the problems of Claude Puel's time in charge of the Saints.
The Frenchman led the club to an eighth-placed finish and a first major cup final since 2003 but paid the price for a dull brand of defensive football, Southampton netting just 41 goals in 38 Premier League games, and was sacked in June.
Pellegrino has so far yet to prove himself capable of bringing the kind of exciting and entertaining style of play he promised to imprint upon his appointment, with his possession-based approach so far resulting in several stagnant performances.
And they travel to L4 to face a Liverpool side who have regained their confidence with three straight victories in all competitions, scoring 10 goals in that time.
The hosts' last outing saw them thrash West Ham United 4-1 and regain some of the attacking verve that had been absent during a poor spell, with in-form summer addition Mohamed Salah netting twice to continue his scintillating start to his Liverpool career.
Southampton meanwhile have endured a few disappointing results ahead of a daunting festive fixture schedule that pits them against five of last season's top six before the end of December, four of those games coming away from home, with pressure growing on Pellegrino.
Having disappointed in clashes with the league's lesser lights, hopes are not high going into encounters with those expecting to challenge for honours - but Pellegrino will hope for a morale-boosting performance and result as he seeks to demonstrate that his Southampton team can develop a clearly-defined identity.
But Liverpool - likewise - go looking to prove a point; that they have well and truly put their heavy defeat away to Tottenham Hotspur last month behind them and are capable of charting an assault at the top end of the table.
Back-to-back 3-0 wins over Huddersfield Town and NK Maribor, followed by the thrashing of the Hammers, has allowed them to narrow the gap to their top-four rivals but they are in need of greater long-term consistency.
They have yet to win three successive league games in 2017 and they will hope to rectify that here, with their frightening forward line likely to once again be pivotal if they are to do so.
They also have revenge of sorts to reap against this particular opponent, having failed to win - or even score - in four meetings against Southampton last season.
Goalless draws home and away in their two league counters were offset by 1-0 wins for the Saints across two legs in the semi-finals of the League Cup back in January, Liverpool unable to penetrate the Saints' defence.
And on the topic of Southampton's defence, another notable narrative of this weekend's encounter is that it will be Virgil van Dijk's first trip to Anfield since a summer-long saga in which he repeatedly pushed for a move to Liverpool.
Klopp appeared close to landing the Dutchman, whom he made his only centre-back target despite the Reds' defensive weaknesses, only for the South Coast club to accuse their top-flight rivals of illegally tapping up the player.
Despite Liverpool's willingness to spend a world-record for a defender fee of around £75 million on van Dijk, Southampton refuted their approaches even in spite of the defender going on strike and being forced to train away from his team-mates.
With Liverpool's back-line having been their obvious, and sometimes fatal, flaw this term - much is expected to be made of how van Dijk fares against a club that he could still yet sign for in January or next summer.
In addition, Liverpool have no fewer than five ex-Southampton players - with four of those likely to play at least some part in this meeting - to add another facet into a game loaded with interesting reunions.
Liverpool welcome former Saints skipper Adam Lallana and captain Jordan Henderson back to the squad.
Lallana has yet to make his first appearance of the season due to a long-term thigh injury sustained in pre-season and could come off the bench for his long-awaited return.
Elsewhere Henderson missed the win at West Ham and withdrew from the England squad with a thigh complaint of his own.
Sadio Mané, who also joined Liverpool from St Mary's, trained on Thursday after returning from international duty with a slight recurrence of a hamstring injury that caused him to miss five games.
Liverpool will make a late decision as to whether the Senegalese winger is fit enough to be involved.
Another of the Reds' five ex-Southampton players, Nathaniel Clyne, is out until February after undergoing a corrective procedure on a back injury on Monday.
Joël Matip will miss out with an adductor injury meaning Joe Gomez could make his first start at centre-back this term.
Southampton have a near fully fit selection to pick from but will be without midfielder Mario Lemina due to an ankle injury.
The summer signing from Juventus has returned to light training after missing their last two games, but is not yet fully fit.
Centre-back and another summer addition, Wesley Hoedt, was forced to withdraw from international duty for Netherlands with a knee injury but should be fit.
Right-back Jérémy Pied is a doubt with a knock.
Recent form (all competitions)
West Ham United 1-4 Liverpool (Salah x2, Oxlade-Chamberlain, Sturridge)
Southampton 0-1 Burnley (Vokes)
Southampton are unbeaten in their last five matches in all competitions against Liverpool, winning three and drawing two, and are looking to go without defeat across six consecutive meetings for the first time ever.
The Saints could become the first team that Liverpool have not scored against in five consecutive matches in all competitions since Nottingham Forest in 1978.
Liverpool have lost only two of their last 32 Premier League matches at Anfield (W19 D11 L2).
The Reds are looking to earn three consecutive league wins for the first time in 2017.
Jürgen Klopp has yet to beat Southampton in the Premier League (D3, L1) having only faced Manchester United as many teams without claiming victory.
Salah (seven) can equal, or even break, Robbie Fowler's Liverpool record of eight goals in his first 12 Premier League matches for the club if he scores this weekend.
Visitors Southampton have won only four of their 40 top-flight matches at Anfield, most recently a 1-0 victory in 2013 thanks to a Dejan Lovren header.
Liverpool have conceded just one goal in seven home Premier League games this season, coming in a 1-1 draw with Burnley.
Southampton have won just four of their last 19 league games (D7, L8).
The last three Southampton players to score at Anfield - and the only Saints to score on L4 since 2003 - all play for Liverpool (Lovren, Clyne, Mané).
Mike Jones is the man in the middle on this occasion, the 49-year-old overseeing his fifth top-flight game of the season.
Two of those matches have involved Southampton, a goalless opening day draw against Swansea City and an away defeat at Stoke City, and he has handed out 16 yellow cards but no red cards so far.
Jones, whose first Premier League game came in August 2008, has not officiated a Liverpool league match since April 2016 - an away win at Bournemouth.