Adnan Januzaj could retain his place in David Moyes' side after scoring twice against Sunderland in the club's last outing before the international break.
The 18-year-old scored twice in his first start for United to inspire the Premier League champion to a 2-1 victory over Sunderland prior to the international break.
Januzaj may now retain his place on the left flank but Tom Cleverley, who also started the match at the Stadium of Light, is a doubt for the clash against Southampton due to a calf injury.
David Moyes may have Rio Ferdinand available after the defender missed the victory over Sunderland with a groin problem.
United is aiming to avoid back-to-back home defeats in the Premier League for the first time since 2002.
On that occasion the hosts suffered 1-0 defeats to Middlesbrough and Arsenal respectively, as they relinquished their Premier League crown to Arsene Wenger's side.
Moyes' men were defeated 2-1 by West Bromwich Albion in their last home fixture on September 28, as Morgan Amalfitano and Saido Berahino struck either side of Wayne Rooney's effort.
But history is with United as Southampton has only taken one point from 14 Premier League visits to Old Trafford.
Despite the poor record at the home of Red Devils, manager Mauricio Pochettino will be buoyed by his side's defensive exploits thus far this season.
It has conceded just two goals in the Premier League so far in an impressive start to the campaign, and the defense has not been breached since a 1-0 loss away to Norwich in August.
Southampton is on a three-game winning streak having seen off Liverpool at Anfield before home successes against Crystal Palace and Swansea City.
Pochettino's men now have the chance to record back-to-back away victories in the top flight for the first time since September 2001.
Goalkeeper Artur Boruc missed Poland's 2-0 defeat against England at Wembley on Tuesday night with a hamstring injury but should be fit to feature, while Luke Shaw - who missed the Swansea game through illness - is also available for selection.