Jurgen Klopp's side have the chance to once again climb above Manchester City in a tit-for-tat title race, but they face an in-form Newcastle side led by a former Anfield favourite.
Liverpool being three goals down at the halfway stage of a huge Champions League match? Rafael Benitez knows the situation well, having led the Reds to the 'Miracle of Istanbul' in 2005 - arguably the greatest night in the club's illustrious history.
Overcoming that deficit against Barcelona at Anfield on Tuesday might come close to rivalling that, but it is a first domestic title since 1990 which the fans really want, and Benitez could have a hand in denying them that this weekend.
Now spending more time avoiding the Championship than competing in the Champions League, Benitez has nonetheless worked wonders in difficult conditions at St James' Park and can once again enjoy a relaxed end to the season having secured safety.
The Spaniard has unsurprisingly set his sights higher than merely survival, and uncertainty continues to shroud his future at the club as he ponders moving to a team with loftier ambitions ahead of the end of his contract this summer.
Newcastle's form in recent weeks certainly suggests that they can trouble the top half of the table with some investment next season; only Man City, Liverpool, Leicester City and Chelsea have picked up more points from their last 10 outings in the Premier League.
That run has seen the Magpies move 11 points clear of the relegation zone and, while last season's final position of 10th is out of their reach, they are still a point better off than they were at the same stage of the 2017-18 campaign.
It is at home where Newcastle have shone brightest recently, and their turnaround in form so far this calendar year has been nothing short of remarkable.
After winning just two of their first 11 home games this season - picking up a total of seven points and scoring only seven goals in the process - Newcastle have since won six of their last seven, accruing 18 points from the 21 on offer.
Worryingly for Liverpool, that run also includes a shock win over Manchester City, with Newcastle the last team to take any points off the champions courtesy of that January triumph.
A similar upset on Saturday would be bittersweet for a man whose name is still sung by the Liverpool fans, although Benitez is yet to taste victory in any of his five league games against his former side since leaving Anfield.
Recent form: DLLWWD
If Klopp is searching for a pick-me-up following Wednesday's chastening defeat at Camp Nou then he need only remind his players that they will not be coming up against anything like the otherworldly talents of Lionel Messi this weekend.
The diminutive demi-god almost single-handedly took the tie away from Liverpool in midweek with a seven-minute brace that changed a 1-0 deficit - entirely reversible at Anfield - into a 3-0 chasm that leaves the Reds needing one of their greatest ever European nights if they are to reach a second consecutive Champions League final.
Such a defeat will always be hard to stomach, particularly as it could have been so different had Liverpool taken their own chances - Sadio Mane, James Milner and Mohamed Salah all guilty of failing to match Barcelona's killer instinct at the other end.
Perversely, though, there were plenty of positives to take from their joint-heaviest Champions League defeat, having been arguably the better team for much of the opening 70 minutes and seen more of the ball than Barcelona at Camp Nou - a feat very few teams have achieved in recent decades.
Indeed, Klopp went as far as to describe it as his side's best away performance in the Champions League under his tenure - including the run to the final last year when they thrashed Porto and beat Man City on the road.
After the match Klopp was quick to switch his attention back to beating Man City in this season's title race rather than thinking about Liverpool's chances in the reverse fixture, and it will be interesting to see how the Reds respond to perhaps their biggest setback of the campaign so far.
Man City barely broke stride following their Champions League exit at the hands of Tottenham Hotspur, and Liverpool must show similar levels of composure after seeing a 10-game winning run and 19-match unbeaten streak come to an end.
Ultimately there is nothing more the Merseysiders can do if Man City win their final two games of the season against Leicester and Brighton & Hove Albion, but they will at least be determined to take it to the final day and victory this weekend would see a 31st change of leadership in this season's title race, with number 32 potentially happening when Man City host the Foxes on Monday night.
There is still the unlikely scenario that a one-off playoff match could be required to separate the two, but should Liverpool lose at Newcastle then Man City could wrap up the title with a game to spare with victory on Monday.
Regardless of what happens from hereon in it has been a fascinating tussle at the top - just the second time in top-flight history that two teams have made it past the 90-point mark and the first time Liverpool have ever managed it in a 38-game season.
The current crop can stand up statistically to any team from Liverpool's glory years, then, but it is silverware which people remember and ultimately the Reds could cruelly miss out on that this campaign barring a shock somewhere along the way in the final weeks of the season.
Recent Premier League form: WWWWWW
Recent form (all competitions): WWWWWL
Liverpool have been hit by the news that Naby Keita will miss the remainder of the campaign after picking up a groin injury against Barcelona in midweek.
Jordan Henderson replaced the midfielder midway through the first half at Camp Nou and could start at the weekend, with Klopp unlikely to consider resting players ahead of the second leg now that qualification is such a remote prospect.
Roberto Firmino was only deemed fit enough for an 11-minute cameo on Wednesday but is expected to return to the starting XI for this match following a minor muscle tear.
Alexander-Arnold is expected to feature in the second leg as a more attacking option than Joe Gomez, while Andrew Robertson on the opposite flank has also been an offensive weapon this season and needs just one more assist to set a new single-season Premier League record for a defender.
Newcastle possible starting lineup:
Dubravka; Manquillo; Schar, Lascelles, Dummett, Ritchie; Kenedy, Shelvey, Hayden, Atsu; Rondon
Liverpool possible starting lineup:
Alisson; Alexander-Arnold, Lovren, Van Dijk, Robertson; Henderson, Fabinho, Wijnaldum; Salah, Firmino, Mane
Head To Head
Liverpool are winless in their last four visits to St James' Park, losing twice and drawing twice since a 6-0 triumph in April 2013, including a 1-1 draw in the corresponding fixture last season.
Indeed, that six-goal haul six years ago is Liverpool's last away win over the Magpies in more than a decade, although they have won their last two meetings at Anfield and are unbeaten in four home and away.
The reverse fixture was a one-sided Boxing Day affair that saw four different players on the scoresheet as Liverpool moved six points clear at the top of the table with a 4-0 triumph.
We say: Newcastle 0-1 Liverpool
This is a dangerous match for Liverpool, with plenty of warning signs that a shock could be in store. The Reds are coming off the back of an energy-sapping and momentum-killing European night, and playing an in-form team at a ground where they have not had much joy of late. It is a must-win game for the visitors, though, and we are backing them to squeeze to a victory which will take the title race down to the final day.