With 57 Tests to his name, Hodge replaces rookie Tom Wright who shifts to the wing, with Rennie making six changes following Australia's record 48-17 loss to Argentina.
Among those returning from injury are centre Hunter Paisami, reserve outside back Andrew Kellaway, and hookers Folau Fainga'a and Dave Porecki.
With James O'Connor sacked after the Argentina horror show, five-eighth Noah Lolesio will play his first Test against the Springboks at the famous cricket ground.
"It's great to have a number of experienced players back in the mix this weekend," Rennie said on Thursday.
"We understand that respect is earned daily and we get an opportunity to earn it against the current world champions on Saturday afternoon."
The Wallabies' back three were badly exposed by the Pumas' contestable kicking game, with Hodges' selection designed to counter an expected similar game plan by the Springboks.
Elevated from the Australia A squad after a season-ending injury to Tom Banks, Hodge started at fullback in the narrow third Test defeat to England and then came off the bench in the Argentina games.
As well as some much-needed experience in the backs, the Melbourne utility also offers a giant boot to help the Wallabies exit their own half.
Tighthead prop Allan Alaalatoa will start after leaving Argentina due to a family death while lock Matt Philip will partner Rory Arnold, relegating Darcy Swain to the reserves.
The Australians are looking to maintain their impressive record on home soil against South Africa as they are unbeaten in their last seven clashes.
The Springboks' last victory over the Wallabies in Australia was back in 2013 while the home side has won their two previous Tests played at Adelaide Oval with their most recent in 2004.
Wallabies: Reece Hodge, Tom Wright, Len Ikitau, Hunter Paisami, Marika Koroibete, Noah Lolesio, Nic White, Rob Valetini, Fraser McReight, Jed Holloway, Matt Philip, Rory Arnold, Allan Alaalatoa, Folau Fainga'a, James Slipper (c). Res: Dave Porecki, Scott Sio, Taniela Tupou, Darcy Swain, Rob Leota, Pete Samu, Tate McDermott, Andrew Kellaway.