Sir Alex Ferguson's side won a nervy encounter with Fulham in their last game, with new signings Robin van Persie and Shinji Kagawa both getting on the scoresheet.
On paper, their trip to St. Mary's Stadium shouldn't prove as tough a test, but in the Premier League, you just never know.
Here are five bold predictions for this Sunday's encounter.
Not before time, Jonny Evans seems to have recovered from an ankle injury sustained at the end of last season to return to Manchester United's defence.
The Northern Irishman will be a welcome addition to the matchday squad, with the Red Devils' back four having looked particularly leaky so far this season, shipping three goals in only two games.
Meanwhile, Ashley Young is set to miss out, having picked up a knock in last weekend's win over Fulham (via Manutd.com).
With Nani currently looking out of favour at the club, I can well see Welsh stalwart Ryan Giggs making his first start of the season in Young's place on the left flank.
Whether in the starting team or from the bench, I can well see Sir Alex giving new signing Alexander Buttner his Manchester United debut this Sunday.
Patrice Evra hasn't looked his usual dreadful self so far this season, though, and will be hard to displace from the lineup.
Nevertheless, Sir Alex has always been willing to give younger players a chance, and with the two-week international break fast approaching, he may want to blood Buttner as soon as possible.
I, like many, am looking forward to seeing the energetic left-back in action, and hopefully Sunday's game at Southampton will be the time and place.
Sure, the United squad are still adapting to life with Robin van Persie in the team and it will no doubt take a few more weeks before Shinji Kagawa and the Dutchman are on a near-telepathic wavelength.
However, Southampton's defence shouldn't provide much opposition to the prolific striker in his bid to consolidate his position as the Premier League's best goal scorer.
If his strike against Fulham suggested anything, it's that given half a chance, Van Persie can find the back of the net from seemingly impossible situations.
Perhaps this one isn't such a 'bold' prediction after all.
Southampton were able to pull off one of the biggest coups of the summer on transfer deadline day by being able to persuade Gaston Ramirez to move to St. Mary's.
And whilst the young Uruguayan isn't guaranteed a starting spot in Sunday's game, Saints boss Nigel Adkins would be a fool not to give his star signing quality minutes against United.
The attacking midfielder arrives having had a quality season at Serie A club Bologna, where he scored eight league goals in 32 games.
If Southampton are to remain in the Premier League beyond this season, Ramirez will be required to continue his fine goal scoring record.
Shinji Kagawa has already thrilled fans with his excellent link-up play and razor-sharp agility so far this season, proving Sir Alex more than justified in bringing him to United from Bundesliga club Borussia Dortmund.
The Japanese attacking midfielder was named man of the match in the Red Devils' 3-2 win over Fulham, getting on the scoresheet for the first time in the Premier League.
I can easily see him picking up the award again this weekend, even is he doesn't find the back of the net.
It is tantalising to think that Kagawa is still improving as a player, considering how good he already is.