Free-scoring United make the 470-mile round trip to the south coast for a rare Saturday 3pm kick off at St Mary's.
The unbeaten Reds followed up the 4-0 win over Everton last time out in the league with another four-goal salvo against Burton in midweek, and have now hit 24 in eight matches so far this term.
In contrast, Mauricio Pellegrino has endured an indifferent start to his tenure as Saints boss, having encountered the same problems as his predecessor Claude Puel.
The Argentinian took over from Puel in the summer, with the Frenchman sacked after a single season at the helm.
That was despite them reaching the League Cup final and an eighth-placed league finish.
That was a competition in which they fell at the first hurdle this time, however, after a surprise early exit to Championship side Wolves - Saints have failed to score in eight of their last nine home matches.
Having edged past strugglers West Ham and Palace, Southampton were held 0-0 at newly-promoted Huddersfield and have collected five points from a possible 15.
Last season's top scorer Charlie Austin is still sidelined, but the hosts managed to keep hold of Virgil Van Dijk, with the classy, in demand centre-back back in the first team fold.
Marcus Rojo and Zlatan Ibrahimovic remain sidelined, as does the hamstrung Paul Pogba, but United have no fresh injury concerns.
Jose made a raft of changes in the 4-1 Carabao Cup win on Wednesday, with all those rested available and likely to come back into the team for this one.
United's left-hand side will give the boss a selection headache however, following Anthony Martial's man of the match performance against the Brewers.
Luke Shaw also got a run out in that match in a bid to prove his fitness and will be pushing for inclusion ahead of Daley Blind and Ashley Young at left-back.
Jose said: "I see the match tomorrow as a very difficult one, Southampton are a very good club and they are very stable in the way they see football, and their quality.
"It was a convincing win on Wednesday against Burton, but we are not thinking of the momentum, not thinking of the next game's importance in the Premier League match.
"It was important because we go into the next draw and the next stage of the competition but we are not thinking about that in this moment.
"Pogba's injury is a great opportunity for others to play, but I have cover in my squad and I trust my people until he returns."
Form guide: Southampton D W L D L W United W W D W W W
Match odds: Southampton 17/4 Draw 4/5 United 8/11
Referee: Craig Pawson