Red Devils boss Ole Gunnar Solskjaer needs a result after a run of three Premier League games without a victory, including two defeats.
Last Saturday's 4-2 loss to Leicester City has seen United slip to sixth in the table - already five points behind Jurgen Klopp's unbeaten Liverpool.
This Sunday's showdown comes on an incredible day of football with the 247th El Clasico taking place earlier in the afternoon.
Paris Saint-Germain are also facing sworn enemies Marseille while Inter Milan host Juventus later but what are the origins behind these rivarlies?
talkSPORT.com takes a look…
Manchester United vs Liverpool
The Red Devils friction with their Merseyside neighbours has done well to avoid dragging Man City and Everton into the discord.
The tension between the cities of Manchester and Liverpool dates back to the industrial revolution in the 19th century.
Manchester was known for its abundance of textile factories while Liverpool benefited from being a port city and both were thriving.
Yet the Manchester Ship Canal was completed at the turn of the century and ships no longer had to dock in Liverpool - costing the city business and jobs.
The rivalry then moved to the pitch with both teams' history of success often pitting the two clubs against each other in their pursuit of trophies.
United and Liverpool remain England's two biggest clubs in terms of silverware, having lifted a combined 131 major trophies since forming.
Marseille vs Paris Saint-Germain
Lionel Messi, Kylian Mbappe and Neymar might front PSG as one of the biggest clubs in the world now but they were once considered upstarts.
Founded relatively late in 1970, the Parisians usurped Bordeaux as Marseille's chief domestic rivals in the late 1980s and early 1990s.
The two teams went head-to-head in the 1988/89 title race, with Franck Sauzee's 90th minute winner over PSG at the Velodrome in May 1989 effectively sealing OM's first title in 17 years.
In the years that followed, Le Classique's were characterised by their aggressiveness - peaking three years later.
One match, dubbed 'The Butchery of 1992', was destined for war after PSG coach Artur Jorge said his players would 'crush' their visitors.
Marseille president Bernard Tapie hung the comments in the dressing room and the result saw more than 50 fouls committed during the game before Alen Boksic sealed the winner for the away side.
Only last season, Neymar was one of FIVE players sent-off during a post-match brawl in which he punched Marseille player Alvaro Gonzalez.
Barcelona vs Real Madrid
The biggest showdown in European football is synonymous for the division it causes in Spain with the world's best players lining up against each other.
Yet the two clubs weren't pitted against each other as incessantly as they are today until the Spanish Civil War.
Madrid became known as a symbol of the militaria government in the capital while Barcelona was seen as the resistance in Catalonia.
On the pitch, the two LaLiga giants have gone toe-to-toe competitively 246 times with Los Blancos boasting 98 wins to Barca's 96.
Inter Milan vs Juventus
Two of the most successful clubs in Italy meet on Sunday as well in the Derby d'Italia as it is known in Serie A.
A major contributing factor towards the hatred between Inter and Juve dates back to the 1960/61 season in which the two challenged for the title.
An April fixture saw the Nerazzurri win 2-0 only for the decision to be overturned due to a pitch invasion and both were ordered to play again.
In protest, Inter fielded their youth team and lost 9-1 with Juventus legend Omar Sivori scoring a domestic record 6 goals in one match.
Meetings between the two sides in the years since have only added to the friction, with the reveal of the Calciopoli scandals rightly angering Milan.