David Moyes' ninth-place team will be looking to get their next batch of games off with a bang after a difficult start to the season, but it won't be easy task against Mauricio Pochettino's well-drilled, fourth-place side, who will look to press United hard at home.
Considering how difficult the reigning champions have found games against hard-working and technically proficient teams so far, it could be a close-run thing, but much will depend on how Moyes sets up his men.
Hit the button below or use the arrows above for a rundown of how United could line up and what sort of precautions the team must take against the visiting Saints.
Tom Cleverley is out with a dislocated shoulder while Rafael and Rio Ferdinand have each suffered knocks that could yet rule them out from facing Southampton.
Both players' importance to the first team could see them given some extra time to regain their full fitness rather than being rushed back and risking further problems that could hamper United's season.
Similarly, Dani Osvaldo must pass a fitness test in order to make Pochettino's matchday squad. Both the Saints' prodigious young left-back Luke Shaw and commanding in-form goalkeeper Artur Boruc will be unavailable through illness and a hamstring injury, respectively.
Rickie Lambert will lead the line for Southampton, with Adam Lallana looking to feed the striker in the absence of Osvaldo.
United have struggled against small, agile and skilful attackers of late, and with Lambert acting as a more physically powerful foil for Lallana by creating space, distracting defenders and posing a distinct goal threat all his own, this mix of strength and flair will challenge the home defence to step up their game.
Should Lallana and Southampton's other lithe attackers, such as Steven Davis and James Ward-Prowse, slip through, they could have a similarly disastrous impact as Morgan Amalfitano and Saido Berahino's did for West Bromwich Albion in their surprise 2-1 win at Old Trafford in September.
The likes of Wayne Rooney and Shinji Kagawa will also find their space and time on the ball limited with Victor Wanyama and Morgan Schneiderlin forming a fearsome duo in midfield by closing down opponents and breaking up play.
While Shaw and Boruc will be big misses for the Saints, Daniel Fox is an able deputy at left-back who along with Nathaniel Clyne will be seeking to exploit any narrowness on the overlap to further pressure United through overloads on the flanks.
Dejan Lovren and Jose Fonte are one of the league's most in-form defensive partnerships, and although they may not be the greatest individual centre-backs in the division, chemistry and understanding at the back can often go a lot further than just pure talent alone.
They will be trying to force United to take risks in order to find a way through their well-organised lines. Paulo Gazzaniga or Kelvin Davis will deputise for Boruc, but following a number of standout performances, the Pole's boots will not be easy to fill.
GK: David de Gea
The Spaniard is now United's undisputed No. 1 in goal, with his excellent reflexes and early maturity now allied with an increase in confidence and stature between the sticks.
As always, Lambert will test his comfort in the air and strength in the challenge, but considering his form of late, it's an examination that de Gea should pass.
Regardless of a keeper's quality, a clean sheet is never an easy feat without the support of a well-oiled defence, and questions linger over how United's back line will line up against Southampton.
CB: Nemanja Vidic and Jonny Evans
With Ferdinand's availability uncertain going into the weekend, it looks likely that Vidic will start as United's senior centre-back, with Evans, as the second-most experienced defender, adding continuity alongside his captain.
Though Vidic has retired from international football, Evans was in action for Northern Ireland over the break but having been sent off against Azerbaijan in his country's second-to-last qualifier, the week is likely to be one he'd rather forget.
Coming straight back into action for United should allow him to focus his mind rather than overthinking his error while on international duty.
Having played at right-back for England against Poland, Chris Smalling may be another option should Moyes feels that the Englishman's part in his country's qualification success could bring some much needed momentum to the team.
FB: Patrice Evra and Phil Jones
At left-back, Evra should return to action as United's best option in the position, with Alexander Buttner far from ready to truly challenge the Frenchman for his place.
On the right, it's unlikely Rafael will be returned to the side unless completely ready to resume his tough-tackling, high-energy performances at full-back. Should he not recover fully from his knock, Jones is the most likely candidate to start considering his greater attacking threat compared to Smalling.
Alternatively, having told of his desire to leave Old Trafford in search of game time, according to ESPN, Fabio may be thrown a bone to play in place of his brother.
With Cleverley out of action and Anderson out of sorts, Carrick and Fellaini look to be Moyes' only realistic options in midfield.
Though as a partnership the pair lack pace and has looked rather pedestrian when called upon to take control of games, its defensive qualities could useful against Southampton's busy and intense approach to the game.
Fellaini will look to add a physical bite to the side, although the Belgian must ensure he doesn't give away too many fouls.
Meanwhile, fresh from receiving numerous plaudits for his considered and conservative performance as England's midfield anchor against Poland, Carrick will be set up to patrol the space ahead of defence, intercepting loose balls and preventing gaps from appearing in United's lines.
Wings: Danny Welbeck and Antonio Valencia
On the flanks, Welbeck could be deployed on the left, with his excellent work rate and link-up play a potential asset against the Saints' own hard-working wide men.
Based on their club form, Nani should get the nod from Moyes but, like Welbeck, Valencia's greater industry could see him selected to wear down Southampton's left-flank.
The Ecuadorian is another player coming back to the club after a fruitful international break. Having helped confirm his country's qualification that was dedicated to his late friend Chucho Benitez amid emotional scenes, he too may be given the chance to bring some of that impetus back to Manchester with him.
Kagawa, Ashley Young and Adnan Januzaj are other options, and with United's flanks currently one of the least convincing departments of the team, there's an argument to be made for any of the possible combinations to be involved.
ST: Wayne Rooney and Robin van Persie
Both of United's star strikers were in fine form for their countries during the international break.
Van Persie became the Netherlands' all-time top scorer, overtaking Patrick Kluivert with a hat-trick in a 8-1 thrashing of Hungary, while Rooney scored in England's wins against Montenegro and Poland.
Last season, the Dutchman scored a hat-trick against the Saints in a 3-2 away win on the South Coast, while his English striker partner got a brace in United's 2-1 home in the reverse of that fixture in January.
They should be able to outfox Southampton's defensive partnership of Fonte and Lovren, although with supply to the front something of an issue for United at present, Rooney may have to drop deep to split the front two into a one as he toils in the hole and midfield.
Putting it all together, this is how United's 4-4-2 could look against Southampton, with uncertainty over the team's final defensive personnel.
Alternatively, should Anderson start, Moyes could conceivably use the Brazilian in a similar manner to how he's deployed Cleverley of late—in a midfield three of a 4-5-1—while as stated in a previous slide, the set-up of the flanks is an inexact science of late, with no combination certain to start.
If anyone will be thrown in as a wild card, however, it'll Januzaj, although Moyes shouldn't be relying on the enthusiasm of a youth player to patch up the problems of his system.
As for the result, this could be a difficult game for United, and a draw is not out of the question considering their recent problems at home against the likes of West Brom.
Should the team click against the Saints, however, expect a win with a margin of two goals to put Moyes' team and their season back on track.
How do you think United will line up against Southampton? What are your predictions for the result?