Seven points already separate the two sides in the Premier League table, but this will be United's first real test of their title credentials and both teams will go into the biggest match in English football confident of picking up a win.
Liverpool were being touted as genuine title contenders throughout the last international break following a 4-0 victory over Arsenal, but it has been a very different story this time around.
Just one win in seven matches between the international breaks have left the Reds seventh in the Premier League table, without a win from two Champions League games and eliminated from the EFL Cup following a hugely disappointing September.
The gap to the leading Manchester clubs is already seven points, and defeat on Saturday would extend that to 10. While it is still too early to come to any final conclusions regarding the league table, a 10-point deficit would be a very big ask for Liverpool to overhaul considering how impressive both City and United have looked thus far.
Describing this match as a must-win game for Liverpool would be premature - they have only lost once in the Premier League this season and are only one point off the top four, after all - but it is verging on a must-not-lose contest if the Reds have any serious designs on challenging for the title.
Jurgen Klopp's style isn't exactly conducive to favouring not losing over winning, though, and the German is highly unlikely to change his philosophy for United's visit this weekend, despite his side going seven matches without a clean sheet across all competitions and only West Ham United and Crystal Palace having conceded more Premier League goals this season.
The defence has been a long-standing issue which, by his own admission, Klopp is losing patience with, but the growing concern for Liverpool prior to the international break was their wastefulness in front of goal. Many of their dropped points came in matches they otherwise dominated, but were unable to kill off.
Draws against the likes of Burnley and Leicester City - and earlier in the season Watford - are frustratingly nothing new for Liverpool, though, and despite their poor recent form there will be many backing them to win this weekend given their exemplary record against direct rivals under Klopp.
The German has spent just over two years in the Anfield hotseat now, and in that time he has lost only two of his 20 outings against Arsenal, Chelsea, the Manchester clubs and Tottenham Hotspur, often saving their best performances for some of their closest rivals.
It is a record which leaves Liverpool top of the top-six mini-league during Klopp's tenure, although he is yet to record a Premier League victory over United - perhaps due largely to United's style of play being most closely aligned with a 'smaller' club than any other from that 'big six'.
United look like a different beast this season, though, and with Liverpool winless at home since August the visitors may be tempted to attack more than they have on recent visits - something which could play into the hosts' hands.
Recent Premier League form: WWLDWD
Recent form (all competitions): DDLWDD
Following a severely underwhelming debut season on the Premier League front last term, Mourinho's Manchester United are making up for lost time and have set the early pace alongside local rivals City so far.
Having dropped 23 points at home last season, United have begun this campaign with a perfect record in front of their own fans, and they are not far behind on their travels either with a 2-2 draw at Stoke City the only blemish on their away record so far.
Questions still remain over the credibility of their title credentials, though, as while City have already claimed maximum points from matches against Liverpool and Chelsea, this weekend's contest will be United's first big test against a direct top-six rival this season.
Of course, Mourinho's side can only beat what is put in front of them and a 10-match unbeaten streak which includes nine wins is impressive no matter the opponents, but the real tests are still to come for the Red Devils, starting at Anfield on Saturday.
Mourinho will face questions of his own heading into the match having developed a reputation for playing defensive football away to direct rivals in recent years, and the Portuguese boss must decide whether to once again shut up shop - a tactic which has proved effective in the past, not least at Anfield - or look to continue his side's free-scoring streak in front of goal.
United have averaged three goals per game in the Premier League this season and trail only City in the scoring charts, while they have found the back of the net four times in a game on six separate occasions during their last 10 outings - four of which have come in their past five matches.
Saturday's visitors are better equipped to take the game to Liverpool than they were last season, then, but Mourinho may still opt for the safer approach knowing that their hosts tend to struggle more against teams who let them see more of the ball.
Manchester City will be expected to beat Stoke City at home later on the Saturday, though, which could force Mourinho to be more aggressive in order to put the pressure on his local rivals by temporarily moving to the top of the table.
Mourinho has played down the added significance of this fixture between English football's two most successful clubs, but he will know first hand how important it really is, and his own personal rivalry with Liverpool from his days at Chelsea will only add spice to an already mouth-watering contest.
The former Real Madrid boss has not managed a team to a Premier League victory over Liverpool in almost three years, though, while his personal record against Klopp is also underwhelming with just one win from seven previous meetings.
Recent Premier League form: WWDWWW
Recent form (all competitions): WWWWWW
Liverpool have been hit by the news that winger Sadio Mane - only recently back from suspension - is likely to spend six weeks on the sidelines with a hamstring injury sustained on international duty with Senegal.
There were no other major injury problems during the break, although Philippe Coutinho and Georginio Wijnaldum trained away from the rest of the squad on Thursday having been in action for Brazil and Netherlands respectively.
Dejan Lovren pulled out of Croatia's qualifier with Finland but featured in the win over Ukraine and should be fit to start this weekend despite his recent admission about taking painkillers before every match.
Manchester United also suffered an injury blow during the international break as Marouane Fellaini sustained ligament damage for Belgium, leaving Mourinho short in midfield due to the continued absence of Paul Pogba and Michael Carrick.
Fellaini's compatriot Romelu Lukaku did come through the break unscathed after being used sparingly, and a goal for the in-form striker on Saturday would see him set a new club record of eight goals from his first eight Premier League games for the club.
Liverpool possible starting lineup:
Mignolet; Alexander-Arnold; Matip, Lovren, Moreno; Oxlade-Chamberlain, Henderson, Can; Salah, Firmino, Coutinho
Man Utd possible starting lineup:
De Gea; Valencia, Bailly, Jones, Young; Matic, Herrera, Mata, Mkhitaryan, Rashford; Lukaku
Head To Head
Manchester United are winless in their last four meetings with Liverpool across all competitions, although the three most recent editions of this famous fixture have all ended as a draw.
The corresponding fixture last term was goalless at Anfield - only the second time that has happened in the last 50 league meetings between the teams - while at Old Trafford in January United needed a late Zlatan Ibrahimovic goal to cancel out James Milner's first-half penalty.
Liverpool have failed to win any of their last six Premier League games against United, though, and you have to go back more than four years to September 2013 for their last league win over their fiercest rivals at Anfield, when Daniel Sturridge scored the only goal of the game.
We say: Liverpool 1-1 Man Utd
Saturday's match is shaping up to be a fascinating contest - the form book screams victory for United but Liverpool's record against their direct rivals cannot be ignored. Should Mourinho try to attack the hosts then it could be a high-scoring classic, but the Portuguese boss is likely to err on the side of caution again and would probably be content with a point at Anfield.