While the Red Devils sit equal top of the standings with rivals Manchester City, this is the type of match the club has struggled with recently.
Jose Mourinho's men regularly dropped points against mid-table teams last season, and travelling to Southampton is a similar test to facing Stoke City away - who United drew 2-2 against earlier this month.
The Stoke match was reminiscent of many of United's struggles last season and a sturdy Southampton outfit under new coach Mauricio Pellegrino will hope to bring back those nightmares.
Class defender Virgil Van Dijk made his first appearance for the club last weekend since his move to Liverpool failed to materialise, and he could be thrust into the heart of the Saints defence in a bid to put the shackles on the in-form Romelu Lukaku - who has scored five goals in five league games.
Southampton's defence is statistically among the best in the division - having conceded only four goals in five games - with their problems lying at finding the back of the net themselves.
While United have thumped in 14 league goals this campaign, the Saints have only scored four goals - and three of those were in the 3-2 win against West Ham last month.
Striker Manolo Gabbiadini hit the ground running with four goals in his first three games for the club after signing from Napoli last season, but since then has only scored once in 13 appearances and started on the bench in Southampton's last match.
Manchester United will be without star midfielder Paul Pogba, who suffered a severe hamstring injury against Everton last weekend, but have able replacements in Marouane Fellaini and Ander Herrera.
Since Pogba's absence, United's midfield machine has still purred quite nicely but memories linger of their stunted midfield play during the matches without the superstar Frenchman last campaign.
Mourinho's biggest headache will be the selection of his attacking third, with the Portuguese unlikely to select all three of the in-form Marcus Rashford, Anthony Martial and Henrikh Mkhitaryan behind Lukaku.
|BEST BET||VALUE BET|
|Manchester City to win the Premier League at $1.90|
Taking into account United's propensity to struggle in these types of games, Southampton to win or draw at $2.20 represents strong value.
Despite failing to hit the back of the net recently, Gabbiadini is well-priced at $4.00 to score anytime during the match - just maybe wait to see if he is starting the match or not first.
*Prices subject to change