De Gea suffered a groin injury in the 59th minute of Spain's 1-1 draw away to Sweden on Tuesday night.
The keeper, who was making his first start under new Spain coach Roberto Moreno, fell to the ground in obvious pain after clearing the ball up the field and was replaced by Kepa Arrizabalaga.
Although there was no post-game medical report, it looks highly unlikely De Gea will be fit for the weekend, and if he has torn a muscle he will likely be out of action for several weeks.
Rodrigo Moreno scored an injury-time equalizer for Spain to earn them a point and secure their qualification for the 2020 European Championships, but De Gea's injury is a big problem for his club.
Manchester United coach Ole Gunnar Solskjaer is under pressure after the club have suffered their worst start to a season in 30 years, with just two wins and nine points from their first eight matches to sit 12th in the table.
De Gea has started all eight of United's league matches this season, while his understudy Sergio Romero has been limited to one Carabao Cup and one Europa League appearance.