Liverpool travel to Old Trafford in the midst of their worst goal drought for almost 20 years, whereas the hosts are flying high and now have a six-point lead over the champions at the top of the Premier League table.
The pre-match hype for this latest chapter of English football's greatest rivalry may be scaled back compared to their top-of-the-table Premier League clash last weekend, but Sunday's showdown promises to be a significant occasion in its own right.
A place in the fifth round of the FA Cup is up for grabs, and both teams would relish being able to knock their biggest rivals out of the running for a major piece of silverware.
The game could prove to be even more important in the grand scheme of the season, though, with Man United currently on a firm and unerring upward trajectory whereas Liverpool are trending in the opposite direction.
The Premier League champions slumped to a 1-0 defeat at the hands of relegation-threatened Burnley on Thursday night, a result which not only extended their winless league run to five games and goal drought to four games, but also saw them surrender a 68-match unbeaten league run at Anfield - the second-longest run in English football history.
For the run to be ended by a team that went into that game as the top flight's lowest scorers was undoubtedly a shock, but the warning signs had been there in previous games for Liverpool.
Since hitting Crystal Palace for seven before Christmas, Liverpool have scored just once in their last five league games and have failed to find the back of the net in any of their last four - their longest drought since May 2000.
Indeed, the Reds have had a whopping 87 shots since last scoring in the league - including 27 against Burnley - but the concerning element of that will be that only a handful of those shots have come in clear-cut chances.
Jurgen Klopp has acknowledged that his side are lacking confidence following a five-game winless run in the league, but quite how they have so quickly transformed from a team that had scored in every game and a team that remain the league's leading scorers into a team seemingly bereft of belief or ideas in the final third no doubt has him scratching his head.
Heading into this game - and indeed looking ahead to a run which sees five of their next six top-flight games come against teams currently in the top seven - Klopp may take some encouragement from the fact that Liverpool's best spell of football during this recent slump came in the opening half an hour of their last meeting with Manchester United.
The Reds failed to capitalise on that spell of dominance, though, and ultimately left Anfield thankful for Alisson Becker preventing them from losing to the current league leaders.
The FA Cup could provide a welcome distraction from those league woes, and Liverpool's only goals and only win so far in 2021 came in the third round of the competition.
Even that was not entirely convincing, though; Klopp named a strong team despite Aston Villa being forced to field their youngsters due to a coronavirus outbreak, and it wasn't until a flurry of three goals in five minutes on the hour mark that Liverpool were able to pull away from their inexperienced hosts.
The Reds also have a notoriously poor record in the FA Cup during Klopp's tenure, only making it past the fourth round for the first time last season.
Man United, by contrast, have not failed to make it to at least the quarter-finals since 2013-14, and in a stark reflection of the differing fortunes of these two clubs in recent months, many will consider them to be favourites to progress again on Sunday.
In all competitions Man United have now lost just one of their last 12 outings since being knocked out of the Champions League, most recently coming from behind away from home yet again to overcome Fulham on Wednesday night.
Inspired by another wonder goal from the rejuvenated Paul Pogba, Man United answered questions posed by both Leicester City and Manchester City, both of whom had climbed above the Red Devils in the table prior to that trip to Craven Cottage.
The 20-time champions retained their two-point lead at the top of the table having now reached the halfway stage of their season, and victory over Liverpool - even in the FA Cup - will go further to affirming the belief that they really are ready to mix it among the title contenders once again.
It is not something which most Man United fans would have expected at the beginning of the season, but that title race will now be their main priority for the second half of the season.
FA Cup glory would be a welcome bonus to that too, although despite consistent success in getting to the latter stages of the competition in recent times, Man United have only gone on to lift the famous trophy once in the last 16 years.
Manchester United FA Cup form: W
Manchester United form (all competitions): WLWWDW
Liverpool FA Cup form: W
Liverpool form (all competitions): DDLWDL
Liverpool are expected to be without captain Jordan Henderson once again on Sunday after he missed the Burnley game with a muscle strain.
Klopp has played down concerns over the severity of the problem, but the quick turnaround between matches makes it unlikely that Henderson will recover in time to start this weekend.
There was better news on the injury front with Joel Matip returning in midweek and Kostas Tsimikas back on the bench, and the latter could start this game in order to give Andrew Robertson a rare rest.
Other changes could also be in the offing with fringe players such as James Milner, Neco Williams and Alex Oxlade-Chamberlain pushing for starts, while Klopp could look to protect his fragile centre-back options by giving either Nat Phillips or Rhys Williams a run out.
Man United have had an extra day of rest ahead of this game but are still expected to make changes, one of which will see Marcus Rashford return to the starting XI after he sat out against Fulham.
The calibre of the opposition means that Solskjaer is unlikely to weaken his starting XI too much, though, so the likes of Bruno Fernandes, Pogba, Harry Maguire and Edinson Cavani could all still start.
Manchester United possible starting lineup:
Henderson; Wan-Bissaka, Lindelof, Maguire, Telles; McTominay, Matic; Rashford, Fernandes, Pogba; Cavani
Liverpool possible starting lineup:
Alisson; Williams, Phillips, Fabinho, Tsimikas; Milner, Thiago, Jones; Salah, Firmino, Minamino
Head To Head
After almost a year without facing each other, these two sides last met just seven days ago when they played out a largely uneventful goalless draw at Anfield.
That result means that Liverpool are now five games unbeaten against their biggest rivals, while they have lost just one of the last 11 editions of this fixture across all competitions.
However, Man United are unbeaten in their last seven home games against Liverpool - their longest such run since 1990 to 2000 - while the Reds have been eliminated from the FA Cup by their great rivals on nine previous occasions - more than by any other opponent.
Seven of those came in a row between 1948 and 1999, but Liverpool have won two of the last three FA Cup ties between the clubs, most recently prevailing 2-1 at the same stage of the competition in 2012 courtesy of goals from Daniel Agger and Dirk Kuyt.
We say: Manchester United 1-0 Liverpool
Liverpool's attack is too good for their drought to last much longer, but the worrying thing for Klopp is that the chances - not just the finishing - have largely dried up too, to the point where it is difficult to back them to even score at the moment.
Things are tighter at the other end despite their defensive injury problems, but Man United have a number of attacking players in much better form than those of Liverpool and that could ultimately prove to be the difference in this tie.
It may be another tactical battle for long spells, but on current form we expect the hosts to progress through to the fifth round and for Liverpool's woes to deepen.
Top betting tip
body check tags ::