When: Sunday August 22, 2pm GMT
How to watch: Sky Sports
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Manchester United will be hoping to back up their fine 5-1 opening day win over Leeds when they travel to the St Mary's on Sunday.
Spearheaded by Bruno Fernandes, the Red Devils were in irresistible form at Old Trafford, although they won't be taking anything for granted on the south coast.
Southampton, meanwhile, lost their first match of the season to Everton but they showed enough to be hopeful of enjoying another solid season in the Premier League.
Last three meetings
Manchester United 9-0 Southampton (February 2, 2021)
This was one of those thrashings that was so brutally comprehensive that if it had been shown on the old vidiprinter they would confirm with a '(nine)' out of fear people will assume they had made a typo.
Alexandre Jankewitz was sent off for the Saints in the second minute, so it was a bit of a mismatch from the off.
That said, Southampton still failed to show any kind of spine and Man Utd were only too happy to take full ruthless advantage.
Southampton 2-3 Manchester United (November 29, 2020)
The last time these two met at St Mary's it was once again memorable for Man Utd, albeit in a different way.
Jan Bednarek and James Ward-Prowse had Southampton in a commanding position at half-time, and they looked odds-on to run out the winners.
They had reckoned without Edinson Cavani, though. The Uruguayan was introduced from the bench at half-time, and he created one before scoring two himself - including an injury-time winner - to completely turn the match around.
Manchester United 2-2 Southampton (July 13, 2020)
It was Southampton who tasted injury-time joy in this one as Michael Obafemi bagged a 96th-minute equaliser.
The match exploded to life from the off with the first 23 minutes providing three goals. Stuart Armstrong gave the Saints the lead before Marcus Rashford and Anthony Martial fired United ahead.
It looked like it was going to stay that way too, but Obafemi had other ideas.
Southampton 3-1 Manchester United (April 13, 1996)
If you don't remember this one, you have certainly heard of it. It was the time when Man Utd were so embarrassed they claimed their shirts made them invisible.
Southampton went in at half-time 3-0 ahead after goals from Ken Monkou, Neil Shipperley, and Matt Le Tissier. Man Utd changed their shirts at the break, with Sir Alex Ferguson protesting that his players could not see their team-mates as they blended into the crowd.
Ryan Giggs replied for Man Utd after the break, but their new blue and white shirts were unable to help them narrow the deficit further.
Premier League head-to-head
Southampton wins: 7
Man Utd wins: 28
Southampton goals: 50
Man Utd goals: 96
Reinvigorated Red Devils
Things have not always felt all that positive in the red half of Manchester since Sir Alex Ferguson sailed off into retirement.
They have always had that look of a club who recruited laboriously in an effort to keep up with much slicker rivals.
This summer has felt very different though, with Jadon Sancho and Raphael Varane offering a serious injection of quality for Ole Gunnar Solskjaer's side.
These are the games - away matches against solid opposition - in which they will have to show their worth, though, and it has generally been a good hunting ground for them in the past.
Testing times for Southampton
Southampton lost three vital players this summer in Danny Ings, Jannik Vestergaard and Ryan Bertrand and it remains to be seen how it will impact them.
Adam Armstrong may lesson the blow of losing Ings, and he made a perfect start by netting on his debut at Everton last week.
The former Blackburn man was prolific in the Championship and he will shoulder the burden of replacing Ings' goals this season.
Vestergaard and Bertrand both went to Leicester City and right now it is hard to see the Saints plugging the defensive gap unless reinforcements arrive.
You look at Manchester United and it's not hard to find goal threats.
Bruno Fernandes is always capable, as is Edinson Cavani, and Mason Greenwood is improving all the time. Then there are the likes of Paul Pogba, Jadon Sancho and Marcus Rashford, too.
It is Greenwood who we are going to back here, though, with the youngster looking to have kicked on considerably over the summer. He can be backed at 15/4 to score the first goal.
James Ward-Prowse's set-piece prowess also makes him a tempting one to back at 9/1 to open the scoring.
Ward-Prowse signed a new five-year deal with the club on Thursday, so a goal will be the perfect way to mark a memorable week for the 26-year-old.