Pogba has been battling an ankle problem and United manager Ole Gunnar Solskjaer confirmed that the 26-year-old has suffered a setback in his recovery.
Solskjaer told Sky Sports: “Paul had an injury, he came back, he worked really hard. He came back and played a couple of games, maybe played through the pain barrier.
“He had a scan after the Arsenal game and maybe needed a few weeks’ rest in a boot so hopefully he won’t be too long, but he won’t make this game, no.”
De Gea was forced off in Spain’s Euro 2020 qualifier against Sweden on Tuesday night and Solskjaer admits he is also likely to miss the Liverpool clash at Old Trafford.
De Gea is set to undergo a scan on a suspected groin injury.
United sit 12th and are 15 points adrift of fierce rivals and league leaders Liverpool ahead of Sunday’s showdown.
Solskjaer was battling a lengthy injury list before the international break and De Gea’s issue further adds to those problems.
But the Norwegian is hopeful Aaron Wan-Bissaka and Anthony Martial may be fit to play some role at Old Trafford.
“I can’t tell you 100 per cent [who] is going to be fit as something might happen,” he added.
“But hopefully Aaron and Anthony will last the training this week and be available for selection. If it’s for half a game or 30 minutes I don’t know but let’s see where they’re at.”
Midfielder Juan Mata believes United can kickstart their season with victory over their arch-rivals.
Writing in his blog on the club’s website, Spaniard Mata said: “On Sunday we have a great chance to change the dynamic and we are all very motivated to take the win.
“We are United, we are playing at home and we will give everything to be able to take the victory that our fans deserve in such a special game.”
Mata said of De Gea’s injury: “The bad news from that game was that David wasn’t able to finish the match due to an injury problem after making some great saves. I hope that it won’t be anything major and he can be back with us soon.”