Since Southampton's return to the top flight in 2012, United have beaten them only once in three attempts at Old Trafford, a 2-1 win three years ago this month.
Wayne Rooney scored both of United's goals that day and his current form has revitalised United's season, taken the heat off manager Louis van Gaal and kept the team in touch with the league pace-setters.
Man Utd players fighting for Van Gaal – Rooney
Rooney has scored five goals in his last four games, including last Sunday's winner in a 1-0 victory at Liverpool, which took United to within seven points of joint-leaders Arsenal and Leicester City.
After the win at Anfield, Van Gaal declared that his side can still win the league for the first time since 2013.
But they will need to improve on their general level of performance and will no doubt be under pressure again on Saturday with many supporters unimpressed by Van Gaal's management and playing style.
Midfielder Juan Mata, left out of the of the starting line-up for the last two games, admits the team has to do better, but believes that there is still an opportunity to push for the top.
Even I'm bored by United admits Van Gaal
"I hope this win (at Liverpool) will give us a boost of confidence and help us play better and keep getting results in order to move up the table," said Mata, who scored the decisive goal in United's 3-2 win at Southampton in September.
"There's a long way to go and there is no team who is showing a great consistency, so everything is still open. For the moment, we have to stay focused and keep the same mentality in our next game against Southampton.
"They have got two convincing wins in the last two games so we must be careful."
United may have Bastian Schweinsteiger back from a knee injury that has kept him out for two games to partner ex-Southampton player Morgan Schneiderlin in midfield.
Auxiliary full-back Ashley Young is a doubt with a knock picked up in the win at Liverpool, but Phil Jones could return to increase Van Gaal's defensive options.
Last weekend's 3-0 victory over West Bromwich Albion moved Southampton back into the top half of the table and helped draw a line under a testing period last month.
James Ward-Prowse, the midfielder, spoke confidently after that game about reviving the club's bid to claim a place in the Europa League for a second successive season.
The arrival of striker Charlie Austin from Queen Park Rangers has only added to the growing optimism at St Mary's.
Austin, 26, has joined Saints in a £4 million ($5.7 million, 5.2 million euros) transfer and manager Ronald Koeman is set to hand the forward his debut at Old Trafford.
"His fitness is OK," said Koeman.
"I was a little bit worried about his fitness, because he came out from a hamstring injury, but he showed his quality, he showed his fitness this week, and normally he will be part of the team for this Saturday."
However, Koeman has concerns over the fitness of striker Graziano Pelle and left-back Matt Targett.
"We have some small problems with players like Graziano, if he is really fit to be part of the team," the Dutchman added.
"Matthew Targett had some little stiffness about last weekend, and tomorrow (Friday) we have our final session, then we make those kind of decisions."
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