The Leicester Tigers scrum-half, who bagged two tries in Saturday's 36-27 defeat to the Springboks, has been replaced by Harlequins' Karl Dickson.
Youngs suffered a shoulder injury during the clash and was replaced by Karl's brother Lee Dickson, who is now in line to start the third and final Test in Port Elizabeth on Saturday.
"He didn't present his injury until the end of the game. When we got back, he was struggling to move it," said England head coach Stuart Lancaster.
"From our point of view, he was excellent for us in the second Test. He really played well and he is devastated."
Danny Care is another candidate to fill the number nine jersey as he bids to resurrect his international career.
Care has been involved in a succession of off-field incidents and was omitted from the Six Nations squad. But the 25-year-old produced an impressive performance against the southern Barbarians last week.
"It won't be any disruption. Both Danny and Lee know the game plans," added Lancaster.
Meanwhile the Springboks could be without Willem Alberts and Pat Lambie. The duo picked up knee and ankles injuries in the victory and continue to be assessed.
The Springboks will also be without Francois Steyn, who is set to get married on the same day.