Yeovil are the lowest-ranked side left in the competition, and face a serious task to overcome 12-time winners United in Somerset.
Yeovil will be bidding to progress past the fourth round of the FA Cup for the first time since the 1948-49 campaign when they welcome Jose Mourinho's United team to Huish Park for what should be a cracking tie.
The Glovers will welcome the distraction of the FA Cup considering that they are struggling towards the bottom of the League Two table. Indeed, a total of 28 points has left the club in 21st position in the fourth tier – just two points clear of Forest Green Rovers in 23rd.
Darren Way's side will enter the match off the back of a 2-1 home defeat to Chesterfield in League Two at the weekend, but they have enjoyed themselves in the FA Cup this season – overcoming Southend United, Port Vale and Bradford City to make the fourth round of the competition.
In truth, it is extremely difficult to imagine Yeovil progressing any further, but there is no question that the club will benefit from the money-spinning tie against the biggest club in English football.
Huish Park will be a sellout on Friday night, but the thought of the second-worst defence in League Two welcoming United with all of their talent is a frightening prospect for the Yeovil supporters, who will not want to take a hammering.
The FA Cup is all about ties of this magnitude, and it would be one of the biggest shocks in the competition's history if the hosts could triumph.
Recent form: DLWDWW
Recent form (all competitions): LLWWDL
United announced on Monday that they had completed the signing of Alexis Sanchez from Arsenal, with the Chilean joining the 20-time English champions in a deal that saw Henrikh Mkhitaryan move in the opposite direction.
Sanchez is expected to make his debut for the Red Devils in this match, but for all of the excitement surrounding the 29-year-old, Mourinho will be keen to keep his players focused as they look to avoid a shock in Somerset.
United have won their last four matches in all competitions – overcoming Derby County at Old Trafford in the third round of the FA Cup earlier this month; in addition to recording victories over Everton, Stoke City and Burnley in the Premier League.
The Red Devils have not yet conceded a single goal in 2018, and they will fancy their chances of booking their spot in the fourth round of the FA Cup ahead of a trip to Tottenham Hotspur in the Premier League next week.
United are 12-time winners of the FA Cup, with their last trophy coming in 2016. This competition has taken on more on importance this season when considering their elimination from the EFL Cup, and indeed Manchester City's 12-point lead at the top of the Premier League table.
Having secured Sanchez, United will be feeling pretty good about themselves as they prepare to make the long trip to Yeovil on Friday night.
The Red Devils have not lost to a lower-league team in the FA Cup since Leeds United beat them at Old Trafford in January 2010, and bar an incredible result, Mourinho's side will march into the fifth round of the competition.
Recent form: WWWWLW
Recent form (all competitions): DDWWWW
Yeovil appealed Otis Khan's red card against Chesterfield in the league at the weekend, but that was unsuccessful. The 22-year-old will therefore miss out on facing the club that he represented as a youth.
As for United, Sanchez could make his debut for United, and Mourinho is expected to make changes ahead of the trip to Tottenham next week.
Romelu Lukaku has been tipped to lead the line, however, with Sergio Romero also replacing David de Gea between the sticks. Daley Blind could feature if the Dutchman manages to shake off a slight problem that ruled him out of last weekend's 1-0 win at Burnley.
Yeovil possible starting lineup:
Krysiak; Dickson, N.Smith, Mugabi, James; C.Smith, Bird, Gray, Green; Zoko, Surridge
Man United possible starting lineup:
Romero; Young, Lindelof, Rojo, Shaw; Herrera, Fellaini, Pogba; Rashford, Lukaku, Sanchez
Head To Head
That was just the third time that these two teams have locked horns in their respective histories, with United also winning the previous two in the FA Cup – 3-0 in January 1938 and 8-0 in February 1949.
We say: Yeovil 0-3 Man United
It is a wonderful story, but it is very difficult to imagine Yeovil picking up a positive result on Friday night. Indeed, we fancy the visitors to march into the fifth round of the competition courtesy of a 3-0 success.