Jones' Welsh international colleague Gethin Jenkins suffered a broken cheekbone in the same match and has also been ruled out of the rest of the tour. However, the Cardiff Blues star will stay with the tour party and will have a review appointment with the surgeon in South Africa on Friday.
O'Driscoll suffered a concussion in the match and began the return to play medical protocol on Monday. However, it soon became clear at the start of the process that he was not going to be ready for a return to action for Saturday's third Test in Johannesburg.
Having led Ireland to Grand Slam glory and Leinster to the Heineken Cup crown earlier the season, O'Driscoll had been desperate to complete a hat-trick of honours with a first series win as a Lion.
Although such a target was no longer attainable following last weekend's defeat to the world champions, O'Driscoll was in line to win his 100th international cap in Saturday's third and final rubber at Coca Cola Park.
The 30-year-old had added six Lions caps to his 93 appearances for Ireland before his 2009 Lions tour suffered the same fate as his second tour four years ago when a shoulder injury ended his participation just minutes into the first Test against the All Blacks.
"Being a part of the 2009 British & Irish Lions squad has been one of the highlights of my career," said O'Driscoll, who made his Lions debut in Australia in 2001 and skippered the tour party in New Zealand in 2005.
"We were unbeaten leading into the Test matches and it is a shame that the results in the Tests did not go our way but sport comes down to fine margins at times. We could easily have won the first two Tests but it wasn't to be.
"I have decided to return home to my family this week after a very long season and to ensure I give myself every opportunity to recuperate."
Jones, who started Saturday's second Test having been a second-half replacement in the first, dislocated his right shoulder shortly after half-time in Pretoria.
He received hospital treatment in order to have the shoulder put back into place and will now join O'Driscoll in returning home for further specialist opinion and treatment.
"It is always disappointing to be ruled out of a Test series through injury but I am proud of what the squad and I have achieved on the tour," said Jones.
"Personally, I will always remember playing in the two first Tests and especially running on for my debut in the starting XV at Loftus Versfeld. My heart will be with the boys on Saturday."
With just one match remaining on the tour the Lions will not call for replacement players.
The two other players who suffered injury in the second Test, Tommy Bowe and Jamie Roberts, continue to be assessed on a daily basis but at this point they are making encouraging progress.