The Red Devils will be looking to build upon their last-gasp 1-0 win over Swiss side Young Boys in the Champions League group stage in mid-week.
Manchester United booked their place in the last-16 draw courtesy of Marouane Fellaini’s winner in added time at Old Trafford.
The 20-time English champions have failed to win their last two Premier League games to lose ground on the top four.
Manchester United lost 3-1 to defending Premier League champions Manchester City at The Etihad before November’s international break.
The Red Devils were held to a surprise goalless draw with struggling Crystal Palace at Old Trafford last week.
Southampton, on the other hand, have failed to secure a win in nine games since a 2-0 victory over the Eagles at the start of September.
Former Arsenal midfielder Merson is tipping that Manchester United will secure a comfortable victory over relegation candidates Southampton on Saturday evening.
“I’m not sure how this game will go, and that shows you where Manchester United are,” Merson told Sky Sports.
“They are playing away at a team who’ve only won one game at home in a calendar year and I should be saying banker away win. United are fighting for the top four, but we’re only just going into December and they’re out of the title race by a million miles. It’s unheard of for Manchester United.
“I’m going to go for them to win but I wouldn’t be shocked if they didn’t. There must be something wrong at Southampton for them to be the way they are though, they can’t buy a game, and the result at Fulham was a shocker. The way it’s going, they’ll be playing Portsmouth next season.”
Manchester United are in seventh position in the Premier League table and eight points adrift of fourth-placed Chelsea FC.
The Red Devils have collected 10 points from their seven games on the road in the Premier League this season.
Mourinho’s side have lost to Brighton, Manchester City and West Ham in away games in the English top flight in the current campaign.
MORE: Man United latest news
MORE: Arsenal latest news
MORE: Chelsea latest news
MORE: Liverpool latest news