United suffered a blow before they had even kicked a ball in the new Premier League season, with fullback Rafael da Silva ruled out for ten weeks with a dislocated shoulder, suffered in training.
Ferdinand lasted 76 minutes of United's opening game before limping off and manager Sir Alex Ferguson later revealed that the centre-back would be out until the start of October.
It means Ferdinand, 32, will miss the games against Arsenal and Chelsea and England's two Euro 2012 qualifiers against Bulgaria and Wales.
Fellow central defender Nemanja Vidic also succumbed to injury on Sunday, struggling with a calf problem with the opening minutes before eventually coming off just after half-time.
"Rio has a hamstring injury. He will be out for six weeks,'' said Ferguson. "With Nemanja, we hope it is a nerve in his calf. He felt it prior to the game but he wanted to play. That may be a couple of weeks.''
With three key players out, Ferguson suddenly has a worrying list of defensive problems ahead of a difficult start, that now pits his side against Tottenham and Arsenal at Old Trafford over the next fortnight.
The bright spot for Ferguson is the anticipated return of Patrice Evra from a knee injury against Spurs next Monday.
"We can always put Fabio on the right if we need to. We also have Chris Smalling, so we will get through,'' said Ferguson.