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.
Tottenham vs Manchester United player ratings
Tottenham vs Manchester United player ratings
1/22 Hugo Lloris – 6 out of 10
The keeper made a handful of crucial saves today to keep his side in the lead. He commanded his box well and was quick off the line.
2/22 Kieran Trippier – 4 out of 10
The defender struggled to keep up with the pace and ability of Martial. Was on the backfoot for much of the game.
3/22 Toby Alderweireld – 6 out of 10
He held the line well at the back and made a number of crucial interceptions and blocks.
4/22 Jan Vertonghen – 6 out of 10
It was a disciplined display at the back, but at times he was dragged out of position in the hunt for possession.
5/22 Ben Davies – 7 out of 10
Davies assisted Wanyama’s goal in sublime style and his deliveries into the area throughout were problematic for United.
6/22 Eric Dier – 6 out of 10
Dier used possession well and continued to provide service for the forwards throughout.
7/22 Victor Wanyama – 7 out of 10
He scored the opener, worked relentlessly and his passing was faultless.
8/22 Christian Eriksen – 8 out of 10
As always with Eriksen, his deliveries were remarkable. His ability to pick a player out within a group is simply sublime.
9/22 Dele Alli – 8 out of 10
His movement off the ball upset United and caused chaos within their defence. He tested De Gea on several occasions – top display.
10/22 Son Heung-min – 6 out of 10
An energetic display, but it would have been encouraging to see him shoot more.
11/22 Harry Kane – 7 out of 10
He scored Tottenham’s second which capped off a terrific display from Spurs’ main man.
12/22 David De Gea – 7 out of 10
De Gea made several saves to prevent Tottenham extending their lead. Very dominant goalkeeping from the 26-year-old.
13/22 Eric Bailly – 7 out of 10
Held his position well at the back and was excellent in the air. A disciplined display from the 23-year-old.
14/22 Chris Smalling – 5 out of 10
He struggled to keep up with the movement of the Spurs forwards and, as a result, he was repeatedly dragged out of position.
15/22 Phil Jones – 6 out of 10
Jones held the line at the back reasonably well and controlled the United defence. A textbook display.
16/22 Daley Blind – 5 out of 10
Blind lunged into challenges, which left the United defence vulnerable at times.
17/22 Michael Carrick – 6 out of 10
As always, his vision when in possession was impressive. He was pumping balls up to the forwards relentlessly.
18/22 Axel Tuanzebe – 7 out of 10
The youngster held his own out there against a quality strike force. Made a number of vital tackles and interceptions.
19/22 Jesse Lingard – 5 out of 10
Lingard looked lost at times and was drifting into the background of the game. Needs to do more when he is in possession.
20/22 Juan Mata – 6 out of 10
He was impressive in possession, but it would have been encouraging to see him with more of the ball.
21/22 Wayne Rooney – 5 out of 10
He scored United’s only goal, which went some way to redeeming his poor defensive play.
22/22 Anthony Martial – 7 out of 10
His energy and pace provided a positive prospect for United. He troubled the Spurs defence with his trickery and footwork.
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."