O'Driscoll missed the European trip to Saracens and the Magners League wins over Connacht and Edinburgh but has been given the all clear to play for his country.
The triple Lions tourist will take his place as Ireland captain for the Dublin battle with the Springboks in the first international at the new Aviva Stadium.
"I feel good and I'm looking forward to the team coming back to what is essentially our home," said O'Driscoll.
"We've enjoyed our time at Croke Park but now we want to make some memories at the new stadium. It would have been disappointing to miss the first game at the new Aviva so I'm looking forward to playing."
Ireland head coach Declan Kidney has named an all-Leinster backline, with the exception of Ospreys wing Tommy Bowe.
Gordon D'Arcy joins O'Driscoll in midfield, while Jonathan Sexton starts at fly-half ahead of Ronan O'Gara.
Sexton is partnered at halfback by clubmate Eoin Reddan, with Rob Kearney at full back and Luke Fitzgerald named on the left wing for his first Test in close to 12 months.
With Munster captain Paul O'Connell and Jerry Flannery both absent through injury, Mick O'Driscoll and Rory Best are chosen at second row and hooker respectively.
Kidney is yet to confirm his final member of the matchday 22, with a decision to be made between Andrew Trimble, Paddy Wallace and Keith Earls later this week.
As well as Saturday evening's match up with the Boks (kick off 5.30pm), Ireland also face Samoa, New Zealand and Argentina this month.
Ireland
15 - Rob Kearney (UCD/Leinster)
14 - Tommy Bowe (Ospreys)
13 - Brian O'Driscoll (UCD/Leinster) (capt)
12 - Gordon D'Arcy (Lansdowne/Leinster)
11 - Luke Fitzgerald (Blackrock College/Leinster)
10 - Jonathan Sexton (St. Mary's College/Leinster)
9 - Eoin Reddan (Lansdowne/Leinster)
1 - Cian Healy (Clontarf/Leinster)
2 - Rory Best (Banbridge/Ulster)
3 - Tony Buckley (Shannon/Munster)
4 - Donncha O'Callaghan (Cork Constitution/Munster)
5 - Mick O'Driscoll (Cork Constitution/Munster)
6 - Stephen Ferris (Dungannon/Ulster)
7 - David Wallace (Garryowen/Munster)
8 - Jamie Heaslip (Naas/Leinster)
Replacements
16 - Sean Cronin (Buccaneers/Connacht)
17 - Tom Court (Malone/Ulster)
18 - Donnacha Ryan (Shannon/Munster)
19 - Denis Leamy (Cork Constitution/Munster)
20 - Peter Stringer (Shannon/Munster)
21 - Ronan O'Gara (Cork Constitution/Munster)
22 - Keith Earls (Thomond/Munster)/Andrew Trimble (Ballymena/Ulster)/Paddy Wallace (Ballymena/Ulster)
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