The reverse fixture saw United squeak through 3-2 winners at St Mary's through a Robin van Persie goal in additional time, but United will be aiming to make a much easier job of it this time around.
The appointment of Southampton's new manager Mauricio Pochettino polarized opinion, with some feeling the sacking of former manager Nigel Adkins was harsh. However, the Saints have so far played well under the new manager, his one game in charge ending in a good draw against Everton—incidentally, it was Southampton's first goalless draw in two years.
United have most of the squad back to full fitness and playing, which will pose a selection dilemma for Sir Alex Ferguson.
GK: David de Gea
In the midst of all the criticism aimed at David de Gea for the late goal United conceded against Tottenham Hotspur, Sir Alex emphasized his faith in his young goalkeeper by starting him in the FA Cup tie against Fulham. The Spanish shot-stopper repaid the manager's faith as United ran out 4-1 winners.
LB: Patrice Evra
United's No. 1 left-back Patrice Evra was not rested for the FA Cup against Fulham, but instead played the full 90 minutes. It's highly likely that he'll be dropped for this important league game unless he is injured.
Despite all the headlines that Robin van Persie has made since his arrival at Old Trafford, there is a strong case for inserting Rafael as United player of the season so far. The Brazilian full-back has matured into his role in the team, and United have been better for it.
CB: Nemanja Vidic
Clearly still one of the best defenders in world football, the Serbian defender was rested for the FA Cup, but should regain his place in the starting lineup against Southampton.
CB: Rio Ferdinand
The England international was also rested against Fulham, with Sir Alex opting to give a run out to Phil Jones and Chris Smalling. It is clear to see that Sir Alex is desperate to get a bit of continuity and solidity in defense going, so Ferdinand is the perfect choice for this moment.
CM: Michael Carrick
LM: Shinji Kagawa
RM: Antonio Valencia
It is astonishing to think that 56 points on the board so far this season is a record for Sir Alex Ferguson's side and perhaps it shouldn't be when his firepower in midfield—certainly against Premier League opposition—is considered.
The return from injury of Anderson has lifted United's midfield and added mobility as well as a few more ideas to United's general play.
Michael Carrick's transition-player role has worked brilliantly for United this week, especially his link-up plays with whichever players he has been partnered with.
Sir Alex has taken a shining towards starting Shinji Kagawa from the left. The Japanese international has been often good but not always great, although it seems like merely a matter of time before that changes. Ryan Giggs is also an option.
On the right, the big positive with playing Antonio Valencia is that he links up with Rafael better than any other United winger and is willing to defend when asked to do. Of late, the Ecuadorian's form has dipped, making Nani's injury return interesting. Sir Alex will likely go with the Ecuadorian after starting him on the bench in the Fulham match, but he may be tempted to go with Nani after he had a good game against Fulham.
SC: Wayne Rooney
SC: Robin van Persie
Despite Javier Hernandez's 14 goals, Wayne Rooney and Robin van Persie are quite clearly United's first-choice attack in the league.
Robin van Persie has netted 22 times for United this season so is an obvious starter, while Rooney's brace against Fulham also puts him in line for a call-up.