Coach Heyneke Meyer will now have to plot the way forward without the inspirational leader who returned home on Tuesday after fracturing his jaw in the win over Samoa last Saturday.
De Villiers is the Springboks only casualty from the 31-man squad who initially travelled to England for the tournament.
Scotland’s World Cup plans have also been dealt with a blow with lock Grant Gilchrist tournament ended by a groin injury.
Gilchrist lasted just 19 minutes against USA at the weekend before he was substituted. The extent of his injury was later confirmed as soft tissue damage.
It's a much bleaker picture for Australia coach Michael Cheika, as two of his players are returning home after the first two games.
Just a few days before the Wallabies meet England in a crucial Pool A match at Twickenham, the two-time world champions have lost ball carriers in Will Skelton and Wycliff Palu for the remainder of the competition.
Skelton injured his arm in the win over Uruguay, while Palu suffered a hamstring injury.
Hooker James Hanson will replace Palu while Sam Carter takes the place of lock Skelton.
For England, coach Stuart Lancaster's problems could not get worse.
Having lost to Wales this past weekend, he now also has injury worries.
