Only prop Phil Thiel, number eight Samu Manoa and fullback Blaine Scully have retained their places in the starting line-up from the side beaten 39-16 by Scotland.
Seven of the matchday 23 at London's Olympic Stadium will feature in the tournament for the first time.
USA Rugby chief executive Nigel Melville had set the Eagles a benchmark goal of winning at least one of their four pool games.
Following losses to Samoa and Scotland, the U.S. will be heavy underdogs against the Springboks before wrapping up their campaign on Oct. 11 against Japan.
Team: 1-Oli Kilifi, 2-Phil Thiel, 3-Chris Baumann, 4-Louis Stanfill, 5-Matthew Trouville, 6-Danny Barrett, 7-John Quill, 8-Samu Manoa (captain), 9-Niku Kruger, 10-Shalom Suniula, 11-Zach Test, 12-Andrew Suniula, 13-Folau Niua, 14-Brett Thompson, 15-Blaine Scully
Replacements: 16-Joe Taufetee, 17-Zach Fenoglio, 18-Mate Moeakiola, 19-Titi Lamositele, 20-Cam Dolan, 21-Al McFarland, 22-Mike Petri, 23-Chris Wyles
(Reporting by Justin Palmer, editing by Nick Mulvenney)
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