Ferdinand will be out for six weeks after being substituted with a hamstring injury during Sunday's 2-1 Premier League win over West Brom.
Vidic, who like Ferdinand was replaced during the game, is set to miss the next fortnight with a calf injury.
Rafael faces about 10 weeks out with a dislocated shoulder.
He appeared as a substitute in the 3-2 Community Shield win over Manchester City last weekend but sustained the injury in training.
Ferdinand's problem means he will be sidelined until the start of October and will miss England's upcoming Euro 2012 qualifiers against Bulgaria and Wales.
At club level, he will be out for United's next five games, which see them host Tottenham, Arsenal and Chelsea and travel to face Bolton and Stoke. Rafael, meanwhile, looks likely to miss additional matches against Liverpool and Norwich as well as the derby against Manchester City.
The injuries will lead to an inevitable reshuffle at the back. Patrice Evra, who missed Sunday's match, will come back in at left-back with Fabio likely to switch to the opposite flank and then two from Phil Jones, Chris Smalling and Jonny Evans playing in central defence.
And having had to also cope without winger Antonio Valencia and strikers Javier Hernandez and Michael Owen against the Baggies, United manager Sir Alex Ferguson said: "We've had a torrid time with injuries.
"Young Rafa has done his shoulder in training on Friday and will be out for 10 weeks. He's probably going to have an operation.
"Rio will be out for six weeks. Vida will have checks on Monday, we don't know if it's just a nerve or something, but he could be out for a couple of weeks."
Ferguson said on Friday that Mexico international Hernandez, who has concussion, is more than a week away from returning to training.
Former Arsenal defender Lee Dixon believes the loss of Ferdinand and Vidic will put more pressure on 20-year-old goalkeeper David de Gea, who was at fault for the West Brom goal in the first half.
Baggies new signing Shane Long equalised with a tame effort that beat the Spaniard after United had gone ahead through Wayne Rooney early in the match.
Speaking on Match of the Day 2, Dixon said: "With such a young goalkeeper you would want two experienced centre-backs in front of him to talk him through and that is obviously going to be a problem for the next few weeks.
"But the way Sir Alex is building his squad, he seems to be going for youth and sometimes you will get mistakes."
Ferguson defended his £18m summer signing and backed De Gea to adapt to the Premier League.
He said: "He is young. He will learn. He will come through.
"David's concentration cost him the goal. It was a slack goal to lose but it is an experience for the lad.
"I couldn't believe he never got a free-kick in the second-half. The aerial assault on him was ridiculous.
"It was the same when Peter Schmeichel came. They punished him in his first few games against Leeds and Wimbledon. They gave him a real torrid time.
"In the second half today David was targeted a bit. Not necessarily physically but there were a lot of challenges that should have been free-kicks but the referee decided to play on."
The champions clinched victory nine minutes from time when Ashley Young's low cross took a deflection off Steven Reid and beat Ben Foster in the West Brom goal.
BBC
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