Saturday's clash in Durban will see Bowe, Heaslip and Wallace make their Test debuts for the Lions.
It will be a fourth Lions Test appearance for 2009 tour captain O'Connell, who played in all three 2005 Tests against New Zealand and a fifth for Ireland's Grand Slam-winning skipper O'Driscoll, a Test player from both the 2001 and 2005 tours.
In addition, there are three Ireland players on the bench for this weekend's match.
Second row Donncha O'Callaghan, who captained the Lions to victory over the Southern Kings on Tuesday, out-half Ronan O'Gara, who landed some crucial kicks in that game, and full-back Rob Kearney, who has recovered from a dead leg, have been pencilled in amongst the replacements.
Both O'Callaghan and O'Gara played against New Zealand on the last Lions tour, while Kearney is on the cusp of making his Test debut in the famous red shirt.
Tour manager Gerald Davies said: "Playing South Africa on its home soil is one of the ultimate challenges for the British & Irish Lions.
"South Africa also happen to be the World champions which adds an extra edge to the series, just as it did in 1997.
"The tradition between the Lions and the Springboks is legendary and after the six lead-up provincial matches, the rugby world is waiting with great anticipation for the first Test in Durban this Saturday."
Commenting on the team selection, Lions head coach Ian McGeechan said: "The preparation for the first Test has been very positive.
"It has been a challenge to reach the first Test with an unbeaten record as we have played a variety of provincial teams across the country.
"This challenge is a unique one in the modern rugby calendar in that it comes only in a Lions context these days.
"The players have had to adapt to preparing and playing more frequently. They have answered that challenge.
"It has been 20 years since a Lions team has won all of its' provincial matches leading up to the Test series so it is very satisfying to be in such a position.
"The entire squad and the management have worked hard to create an outstanding team environment.
"Everyone has done this very professionally and it is fair to say that I would not change anything that we have done so far."
He added: "The Test team has been picked on form following the six provincial matches.
"There were some very difficult calls to make as the players as a group and individually have done everything that we have asked of them and performed on the field."
BRITISH & IRISH LIONS TEAM/REPLACEMENTS (v South Africa, 2009 Lions Tour First Test, Saturday, June 20, ABSA Stadium, kick-off 3pm local time/2pm Irish time):
15. Lee Byrne (Ospreys/Wales)
14. Tommy Bowe (Ospreys/Ireland)
16. Matthew Rees (Scarlets/Wales)
17. Adam Jones (Ospreys/Wales)
18. Donncha O'Callaghan (Munster/Ireland)
19. Martyn Williams (Cardiff Blues/Wales)
20. Harry Ellis (Leicester Tigers/England)
21. Ronan O'Gara (Munster/Ireland)
22. Rob Kearney (Leinster/Ireland)