The Saints come into the game off the back of a 5-2 thrashing away at Tottenham Hotspur , and will be hoping to not repeat that score line against the Red Devils.
Here are three key battles which could decide this game at Old Trafford...
3. Paul Pogba vs Oriol Romeu
Paul Pogba made his Manchester United return against the Saints in August of last year. It is fair to say the Frenchman has enjoyed playing against the south coast side, with the ex-Juventus man yet to lose against the Saints.
As for Oriol Romeu, he has been on the end of plenty of defeats against the Red Devils. On Saturday however, the Spaniard will be looking to put his past behind him and give his side a well needed win.
This key battle will determine the outcome of the game, as whoever controls the midfield will control the game. For many Pogba will be the favorite, with the Frenchman already proving in the past that he can get the better of Romeu.
2. Marcus Rashford vs Jack Stephens
Marcus Rashford has terrorised defences for the past two years now, and it seems that the Englishman is going through a dip in form at the moment.
The winger hasn't scored since the defeat to Manchester City in early December. Many critics have been harsh on Rashford in weeks gone by, and many forget that he is still only 20 years of age.
Rashford will be coming up against Jack Stephens, who is a centre half by trade. Stephens has been filling in for the injured Cedric Soares, and has been somewhat unconvincing at times.
The Saints defender lacks pace, and therefore expect Rashford to use his blistering speed against Stephens. This key battle could decide the game in the sense that if Rashford continues to beat Stephens, then the Saints could be in for a thrashing.
1. Romelu Lukaku vs Maya Yoshida
The news of Virgil van Dijk's transfer away might have come as good news to Romelu Lukaku, with the Belgian most likely preferring to play against Maya Yoshida instead of the soon to be Liverpool man.
Lukaku's recent record in front of goal does not boast well for him, however the Saints have conceded 11 goals in their last four games, and therefore Lukaku will be confident of snatching at least one goal.
As for Yoshida, it won't be an easy task to keep Lukaku quiet, however he will be somewhat confident heading into the game, as he knows that the Belgian is not at the top of his game and therefore he could be easier to handle.
Lukaku must bully Yoshida on Saturday evening if he is to win this key battle and win the match for his side. As for Yoshida, keeping one of United's main threats quiet could possibly ensure his side at least a point.