The Red Devils are one of only three teams to deny Jurgen Klopp a top-flight victory since his appointment on Merseyside two years ago.
His charges have dominated all three domestic fixtures under his tutelage against United in terms of chances created and possession, but have recorded two draws and a defeat.
It will not prove easy to end that cycle as Jose Mourinho will be typically obstructive at Anfield, especially with the pressure on Liverpool to pick up maximum points.
Only Manchester City - courtesy of goal difference - have outperformed the Old Trafford outfit in the league this season while the Reds are seven points off the pace.
Klopp will hope none of his other returnees will be carrying minor or major damage from club duty ahead of a testing schedule.
Philippe Coutinho and Roberto Firmino have a 6,000-mile journey to endure from Sao Paulo after Brazil eased past Chile 3-0 to wrap up their World Cup qualifying campaign and are only expected at Melwood on Thursday for training.
Adam Lallana is continuing his rehabilitation from a thigh injury at the Aspire clinic in Qatar and it is hoped he will be in contention again in mid-November.
Nathaniel Clyne is still nursing a back issue, and like his England team-mate, hasn't featured at all this season.
Neither side have any suspension worries for this fixture.
LIVERPOOL POTENTIAL STARTING LINE-UP
Mane's unavailability is a gigantic setback, but Klopp does have more options to alter things than he did last season when the 25-year-old was absent through his participation at the Africa Cup of Nations, and later through meniscus damage in his left knee.
Coutinho could easily move into the front three, while Alex Oxlade-Chamberlain could feature there or in his preferred midfield role as he targets a first league start at Liverpool. Daniel Sturridge and Dominic Solanke are also options to slot into the attack while the Reds boss could tinker with his formation as was the case at the end of last season sans Mane when a diamond was used.
A more detailed look at the ways the hosts could line up without the speedster can be found here, while Klopp's thinking around his XI will centre around their conditions following international duty.
Without fully knowing the fitness levels of the returnees and with the manager only set to provide an update at Friday's press conference, it is difficult to predict the potential line-up.
If there are no further concerns, Emre Can should take his place in midfield and then there is a decision over whether to keep Gini Wijnaldum as the other player in front of Jordan Henderson, use Coutinho there or Oxlade-Chamberlain while also thinking of who would be the best bet as the left forward.
Alberto Moreno is expected to continue at fullback despite Andy Robertson running him close, while on the right flank, Trent Alexander-Arnold - who made his league debut last season at United - and Joe Gomez will be competing for the spot.
Klopp could also opt to use Milner in either of those positions or in midfield if required.
MAN UTD TEAM NEWS
Mourinho insists there will be no special preparations for this encounter and he is expected to revert to his more conservative approach away from home against a rival despite United's stellar start to the campaign. "When you are in a big club, when you are a big player, when you are a big manager, every game is important," he said.
"You cannot look at some matches as cup finals and other matches differently. For me, every match is a cup final and I've been like this all the time.
"It's three points not four. If we are at a moment in a season where the duel between the two teams ensures the result will mean more than three points, than yes. Sometimes a draw or even to lose by a certain goal difference is important. In this case, it is not important. It's just a three-point match. That's the way I approach it.
"It's good it's that way for me. It's good to do it without any added pressure or emotion. I have to do it always in a professional way. It's the right example for my players to prepare for the Liverpool game.
"Do I like to go to Anfield? Yes, I love it. Do I like to play against Liverpool? Yes. I like amazing stadiums, the best opponents but the preparation is not different. It's just a match."
"From what I read, I don't think he can play the match," Mourinho said. "Another one plays and it's no problem for me. Not just Ander [Herrera]. We trust every player. We lost players last season and we lost players this season. With our way of thinking and feeling, it really is no problem.
"One player not playing means another one plays. It's an opportunity for another one and we trust them. We never hide behind this or that player or this or that injury. We trust the ones that are going to play."
Paul Pogba has been out of action since the 3-0 Champions League victory over Basel on 12 September with a hamstring injury while Michael Carrick has missed the last two games with an unspecified knock.
There were concerns of an ankle issue for Romelu Lukaku, who sat out Belgium's victory over Bosnia, but he featured in Tuesday's hammering of Cyprus.
Phil Jones is doubtful after withdrawing from the England squad with an injury, while Marcos Rojo and Zlatan Ibrahimovic (both knee) miss out as they continue their recoveries.
BEST OPTA MATCH FACTS
Jurgen Klopp has lost just one of his seven competitive meetings with Jose Mourinho as a manager (W3 D3 L1).
Since Jose Mourinho took charge of Manchester United ahead of 2016-17; these two clubs have won the exact same number of points in the Premier League (88). Liverpool have scored 16 more goals (91 v 75) but have conceded 23 more (54 v 31).
Romelu Lukaku scored four goals in his first four Premier League games versus Liverpool, but has since netted just once in his last seven. Indeed, he has failed to land a shot on target in five of those seven games.
TV COVERAGE & KICK-OFF TIME
Kick-off is at 12:30pm BST and the match will be televised live in the UK on Sky Sports Main Event.