Since Sir Alex Ferguson retired at the end of the 2012-13 season, Southampton have lost just one of their five away meetings with United in the Premier League.
The Red Devils will need to put that right this weekend if they are to maintain their forward momentum and keep pace with top-four rivals Arsenal, whom they face next week, four days after a trip to Paris Saint-Germain in the Champions League.
Before those difficult away matches is this home meeting with Southampton, and Sports Mole has taken a look at how United could line up against the Premier League strugglers.
Out: Nemanja Matic (muscle), Antonio Valencia (muscle), Ander Herrera (hamstring), Juan Mata (hamstring), Jesse Lingard (hamstring)
Doubtful: Anthony Martial (groin), Matteo Darmian (groin), Phil Jones (illness)
Rashford even made it onto the field and is now expected to return to the starting lineup against Southampton.
Alexis Sanchez failed to impress during his rare start last time out, as was the case with midfield man Fred, but a lack of other options means that the Chilean forward may well retain his place on the left of the front three.