The top team in the EPL has not lost any match since early December, but it will need to start getting more victories than draws if it wants to stay ahead of Manchester City.
Meanwhile, Southampton is pulling itself up from the bottom of the standings with four draws and a win in the past five league matches.
This should be a tough contest from beginning to end. Here is everything you need to know about the league battle.
When: Wednesday, Jan. 30 at 3 p.m. ET
Where: Old Trafford, England
TV: ESPN2, ESPN Deportes
Live Stream: ESPN3
What They're Saying
Sir Alex Ferguson has been with United for a long time, but he gave his current squad some high praise. According to Oliver Platt of Goal.com, the boss said that this could be his best team ever:
When you look at those lads up front, if they can each get to the 20 mark, we will really be in business. The options we've got now all round the park, if we can keep everyone fit, are as good as I've had in my time here.
The Red Devils are certainly loaded with talent, and this could be scary for the rest of the clubs in the EPL and rest of the world.
Manchester United Player to Watch: Robin van Persie
When Robin van Persie came over from Arsenal, fans knew he would provide a boost to the offense. However, he has been simply incredible since joining Manchester United.
The forward leads the EPL with 18 goals and seems to have developed a great on-field relationship with the rest of the club.
He has also been on quite a hot streak lately, scoring 11 goals in his past 11 matches played.
If Southampton has any chance of winning, the defense will need to know where van Persie is at all times.
Southampton Player to Watch: Rickie Lambert
After dominating the English League Championship last year, Rickie Lambert is now playing just as well in the Premier League.
He scored 25 goals a year ago as Southampton was able to earn the promotion. This was only one year after the squad was even lower in League One.
However, Lambert stuck with the club through the bad times and now he is fifth in the league in scoring with 10 goals.
The veteran knows what he is doing on the pitch and is by far the most dangerous offensive weapon Southampton has on the roster.
Prediction: Manchester United 2, Southampton 1
There is no question that Manchester United has the more talented squad. Playing at home should give an additional boost as the group has won 10 of 11 league matches in Old Trafford.
However, the Red Devils have had some trouble closing out matches, and Southampton is playing just well enough to keep it interesting.
United will control possession throughout most of the match, but the final score will be closer than anticipated.