O'Driscoll will form a centre partnership with Cardiff Blues giant Jamie Roberts, who is one of three players who keeps his place in the side from the weekend. The others are Ospreys try scorer Tommy Bowe and Munster back row man David Wallace, who switches from No8 to openside flanker.
It has been an incredible season to date for O'Driscoll, who led Ireland to their first Grand Slam in 61 years, picked up the 2009 RBS Six Nations Player of the Tournament title and then won a Heineken Cup winners medal with Leinster.
"Everyone is delighted that Brian O'Driscoll, the Irish Grand Slam skipper, will lead the team against the Golden Lions," said tour manager Gerald Davies.
There are a further five players in the starting line-up who were used as replacements against the Royal XV - Mike Phillips, Lee Mears, Phil Vickery, Alun-Wyn Jones and Jamie Heaslip - while Shane Williams drops from the team to the bench.
The selection means that of the 36 players the Lions took to South Africa, only Leinster centre Luke Fitzgerald and Munster lock Donncha O'Callaghan will not have been used in the opening two matches.
Head coach Ian McGeechan knows it is going to be a step up in class from the opening fixture, but is happy with his side's preparations.
"The starting XV is very different to the one that played against the Royal XV on Saturday," he said.
"There are only three players backing up from that match, although six of the replacements have been promoted to the starting XV. This is in line with the policy that all players will play a full match in the first three matches on tour.
"The team has a very solid core with Brian O'Driscoll, Stephen Jones, David Wallace, Phil Vickery and Gethin Jenkins, who are all very experienced internationals and previous Lions tourists.
"David Wallace now has the opportunity to play at openside flanker following his selection at No8 against the Royal XV. Stephen Jones who was a replacement in the last match, but did not get a run, links-up with his Welsh team-mate and scrum half, Mike Phillips, giving the team an experienced halfback combination.
"The team has trained well. We have worked on several key areas following the first match, which has given us a base on which to keep developing our game."
Apart from England flyer Ugo Monye, the Lions will be relying on an all-Magners League back division with Leinster full back Rob Kearney making his Lions debut.
Other Magners League stars hoping to make their Lions debuts will be replacements Ross Ford (Edinburgh), Stephen Ferris (Ulster), Andy Powell (Cardiff Blues) and James Hook (Ospreys).
British & Irish Lions (v Xerox Golden Lions)
15. Rob Kearney (Leinster/Ireland)
14. Tommy Bowe (Ospreys/Ireland)
13. Brian O'Driscoll (Leinster/Ireland)
12. Jamie Roberts (Cardiff Blues/Wales)
11. Ugo Monye (Harlequins/England)
10. Stephen Jones (Scarlets/Wales)
9. Mike Phillips (Ospreys/Wales)
8. Jamie Heaslip (Leinster/Ireland)
7. David Wallace (Munster/Ireland)
6. Tom Croft (Leicester Tigers/England)
5. Alun-Wyn Jones (Ospreys/Wales)
4. Nathan Hines (Perpignan/Scotland)
3. Phil Vickery (London Wasps/England)
2. Lee Mears (Bath/England)
1. Gethin Jenkins (Cardiff Blues/Wales)
Replacements
16. Ross Ford (Edinburgh/Scotland)
17. Euan Murray (Northampton Saints/Scotland)
18. Stephen Ferris (Ulster/Ireland)
19. Andy Powell (Cardiff Blues/Wales)
20. Harry Ellis (Leicester Tigers/England)
21. James Hook (Ospreys/Wales)
22. Shane Williams (Ospreys/Wales)
NB. Bold - denotes Magners League players
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