The visitors are chasing an unprecedented record of a fifth straight league win in this fixture, with neither side ever having won five consecutive league matches against each other before, although they have met 166 times in the league alone since 1895.
But with Louis van Gaal having enjoyed victory in every Premier League meeting between United and Liverpool while he was at Old Trafford, they could make history under the floodlights on L4.
This is also the first time that Jose Mourinho, whose relationship with Liverpool fans is well documented, will go up against the Reds as United manager.
The Portuguese boss had a long-running rivalry with former Liverpool manager Rafael Benitez and masterminded the win that helped deny the club a first Premier League title two years ago.
But it is the first time in a long time that United enter this fixture as second-favourites, with Liverpool's stellar form - winning their last five games in all competitions - labelling them as one of the country's form teams.
They look for a fifth consecutive league win for the first time under Jürgen Klopp and the first time since April 2015, a run also ended by a home defeat to United.
Every game this season seems to have been billed as a litmus test for Liverpool, particularly their recent wins over Hull City and Swansea City, with their ability to beat the traditional 'big' teams well known.
But this, again, has the feeling of a massive game for them. They could further prove that they are making great strides with an impressive performance and more so with a result to match.
However, there is also the feeling that Mourinho could halt them in their tracks given the nous he has shown of doing so in the past. United have twice as many wins, with 12, as any other Premier League side at Anfield and they are fully capable of securing the three points.
It could be a blockbuster clash if both teams perform to their potential, both sides having experienced ebbs and flows this season - though United more so than the home side.
The Red Devils have won their last three games, having lost three before that which also followed a three-game winning streak. Yet, while the optimism of the first few weeks of the season has somewhat faded, they still have a star-studded squad which will inevitably improve as soon as they begin to click.
Liverpool, meanwhile, are at their best ever point under Klopp - their encouraging displays and scintillating attacking even prompting suggestions of a title challenge this term, with this another game seen as another chance for them to prove they are ready for one.
Yet, as the cliché goes - recent form can often prove irrelevant in a fixture of this magnitude and it looks certain to be a keenly-contested 90 minutes between the two.
The impact of the result on the confidence of either side could be critical. The stakes have only been so high for both teams on few occasions, and it's for that reason that Monday night is a game that all involved will be relishing.
Liverpool midfielders Adam Lallana and Georginio Wijnaldum are both set to miss out with groin and hamstring injuries respectively.
Lallana sustained his problem in the 2-1 win over Swansea a fortnight ago and was still not back in training earlier this week, while Wijnaldum too was missing at Melwood after pulling up on international duty.
That could mean a first league start this season for Emre Can, who has struggled for fitness for much of the campaign, while Philippe Coutinho could drop into central midfield as he did at Swansea.
Other possible alterations could see Marko Grujic make a full league debut, or the experienced Lucas Leiva step in, with Daniel Sturridge in the frame for a first start if Coutinho drops deep and - as expected - Sadio Mane and Roberto Firmino both start.
Defenders Dejan Lovren and Nathaniel Clyne have shaken off groin and knee knocks and are expected to return to the starting line-up, while Klopp has a decision to make between Loris Karius and Simon Mignolet in goal.
Mourinho handed his players a long weekend off over the international break and has just one missing player for the short trip down the M62.
United are still without Phil Jones, who is back in training but yet to return to full fitness after a lengthy lay-off, who is still making his way back a severe knee injury, but Luke Shaw could start at left-back.
The Englishman was thought not quite fit enough to be included in England's squad for their recent World Cup qualifying double header but is in contention to feature here.
Jesse Lingard could start out wide, with Marcus Rashford, Anthony Martial and Juan Mata among those competing for attacking positions.
Summer signing Henrikh Mkhitaryan, who played under Klopp at Borussia Dortmund and was once a Liverpool transfer target, is also in the frame to feature after coming back from a thigh muscle strain. He requested not to play for Armenia last week to find full fitness.
Wayne Rooney, having been the source of debate over the international break when he was dropped for England's draw in Slovenia for which Liverpool captain Jordan Henderson led the team in his absence, is another hopeful of starting.
His big-game experience could see him favoured, perhaps in the No.10 role with Ander Herrera and Paul Pogba having formed a solid partnership in central midfield in recent games.
Head-to-head league record:
At Anfield: Liverpool - 39 wins. Draws - 19. Manchester United: 25 wins.
At Old Trafford: Manchester United - 42 wins. Draws - 25. Liverpool: 16 wins.
Overall: Liverpool - 55 wins. Draws - 44. Manchester United - 67 wins.
Most recent meeting: Manchester United 1-1 Liverpool (Martial pen, Coutinho) - Europa League Last 16 second-leg (1-3 on agg.), 17 March 2016.
Form in Premier League: DWWWW
Form in all competitions: WWWWW
Form in Premier League: LWWWD
Form in all competitions: WLLWD
Liverpool have not lost three straight home league games to Manchester United since January 2005.
United have won their last four league games against Liverpool and seven of the last nine in total.
Liverpool's run of four consecutive losses versus United is their worst since losing five in all competitions against them back in March 2008.
Liverpool have lost more league games to Manchester United than to any other team, with 67 defeats.
The last time these two teams drew in the Premier League was a 1-1 draw at Anfield in October 2011.
The Reds haven't kept a clean sheet in their last nine league games.
Jürgen Klopp has won three of his five meetings against Jose Mourinho as manager, drawing one and losing another.
United have only won one of their last four league games, conceding seven in that process.
Wayne Rooney needs one more away goal in the Premier League to become the outright top goalscorer away from home. He is currently joined by Alan Shearer on 87.
Rooney also has six goals in this fixture, two off the Premier League era record of Steven Gerrard - who scored eight.
Controversially, Manchester-born Anthony Taylor is the man nominated to oversee proceedings on Merseyside.
The 37-year-old is said to support non-league outfit Altrincham but still lives only six miles away from Old Trafford and has been awarded the game.
Many have criticised the decision, not least Mourinho. The United boss told journalists at his pre-match press conference that it will be "difficult" for the man in the middle to produce a "very good performance" because of his background.
He has shown 23 yellow cards and no red cards so far this season and every decision is no doubt likely to be scrutinised over.
Taylor has been in the Select Group of Referees since 2010 and has officiated 145 top-flight games in his career, handing out 485 yellow cards, 10 double yellows, 15 straight red cards and 32 penalties since.