The 24-year-old midfielder's father Fassou Antoine died on Friday and the France international, who already missed Sunday's match at Tottenham, is on compassionate leave and expected to be absent for the match at St Mary's on Wednesday as he returns to his home country to pay his respects.
United boss Jose Mourinho said: "I don't think (he will be available). I think that his dad's funeral has to be between Tuesday and Wednesday in France.
"I don't think that Paul has the conditions to play. We have left him completely free to be back when he thinks he's ready."
Mourinho already has to do without Zlatan Ibrahimovic, Marcos Rojo, Luke Shaw, Ashley Young and Tim Fosu-Mensah for his side's remaining league matches through injury.
Meanwhile, the Portuguese says United's "crazy" schedule is taking its toll mentally and physically ahead of the Europa League final, leaving them facing a fixture pile-up unlike anything he has experienced.
Next week the Reds head to Sweden to take on Ajax looking to win the only major trophy to have eluded them in their success-laden history.
Europa League glory also offers qualification for the Champions League - the only way they can return to the continent's top table after Sunday's 2-1 loss at Tottenham officially put a top-four finish out of reach.
Mourinho has prioritised European success for several weeks now and, like at Spurs, plans to rotate his squad at Southampton, then again in Sunday's Premier League finale at home to Crystal Palace.
Balancing the desire to win with resting players has been difficult, and Mourinho said: "The accumulation of the games, I never had that.
"You know that in all of my career I was never (knocked) out of European competitions in the group phases and in the last 16 I was out only once.
"So I reached the semi-finals 10 times, I go always until the end of the competitions.
"In the League Cup I normally go far. In the domestic competitions cups, I won in Spain, in Italy, in Portugal so I normally have a lot of matches. But like this I never have, I never have.
"This situation of you play a final and the game that you should play that day is going to be postponed until the last week, for the last week! This is crazy."
Join our new commenting forum
Join thought-provoking conversations, follow other Independent readers and see their replies