Ole Gunnar Solskjaer confirmed that Pogba was unlikely to feature in Sunday’s trip to Southampton having not trained at Carrington on Friday morning.
The 27-year-old has been absent from United’s matchday squads since picking up the injury while away on international duty with France.
Solskjaer said that the ankle injury is a separate issue from the one which sidelined Pogba for much of the 2019-20 campaign.
United are also without Pogba’s fellow midfielder Scott McTominay, which may hand Donny van de Beek an opportunity to make his first Premier League start for the club.
“Scott and Paul didn't train this morning, they weren't on the grass, so they look very unlikely for the weekend,” Solskjaer said at his pre-match press conference.
The United manager hopes that Marcus Rashford, Victor Lindelof and Aaron Wan-Bissaka should be fit to play after training on Friday though described the trio as “not 100 per cent”.
“Luke [Shaw] has just started his rehab out on the grass, not with the team yet,” Solskjaer added.
“Jesse [Lingard]'s back from his isolation period, he's back with the group and has had a couple of days training. Apart from that Phil Jones is probably out until after Christmas sometime.”
Pogba played 90 minutes of France’s 4-2 win over Sweden on 17 November yet returned to Manchester with the ankle complaint a few days later, missing the 1-0 win over West Bromwich Albion.
Solskjaer had hoped that the midfielder would recover in time to take part in Tuesday’s 4-1 victory over Istanbul Basaksehir in the Champions League but he was again absent from the matchday squad.
“We know it's gonna be a difficult one,” Solskjaer said of Sunday’s trip to Southampton.
"They've done really well. If you look back over a 30 or 40-game block they're one of the top teams, so they've made great improvements and we know how difficult this game is going to be.
“We drew tice with them last season, it's a game we can make an improvement on.”