A home draw last week at home to Watford got the Saints off the mark, but now boss Claude Puel knows the areas of improvement needed if they are to avoid a defeat against United as they will not be pushovers.
Fonte's potential return leads team news
Saints captain Jose Fonte is a possible returnee, despite missing the season opener at home to Watford due to starting pre-season later than the others following his Euro 2016 triumph with Portugal.
Ryan Bertrand will not feature due to an injury, so it is predicted that Matt Targett is set to continue at left-back.
Manchester United will have their £89m summer transfer Paul Pogba at their disposal after he served a suspension which carried over from his time at Juventus.
But whether Jose Mourinho will unleash the most expensive player in the Premier League in the starting 11 remains to be seen amid doubts he will manage to play the full 90 minutes after only training with the Red Devils for 11 days.
Chris Smalling is also a returnee following a ban and most likely will replace Daley Blind in the starting line-up to partner Eric Bailly at centre-back.
Southampton has won 1-0 on each of their previous two visits to Old Trafford, however, the Red Devils have been unbeaten at home since losing to the Saints back in January with eight wins and three draws so something has to give.
The Saints conceded a staggering 19 league goals away from home last season and also both of their top two goal scorers from 2015/16 - Graziano Pelle and Sadio Mane, have have left over the summer which could have an impact on the goals.
United conceded only nine goals at home last season, which was the best record in the top flight.