Genia, who started the last two tests on the bench, is the sole change to the Wallabies team that lost 28-8 in Cape Town and will be looking to avoid the wooden spoon in their showdown with the Pumas in Rosario (2240 GMT).
He has been preferred to Nic Smith, while flyhalf Bernard Foley has been included on the bench in place of Chris Feauai-Sautia with the potential to make his international debut as a replacement.
Genia came on in the second half at Newlands to help stem the tide of South Africa's attacks after the Springboks, who will be fighting for the title against holders New Zealand in Johannesburg, had taken a commanding 23-3 halftime lead.
"We're working hard on how we want to play the game and Will is obviously a very experienced player," Wallabies coach Ewen McKenzie said.
"We were pleased with the contributions of Nic but Will is proven at this level and we are faced with a very difficult game in a tough playing environment," he added.
"As a result, we've gone for Will's experience to help get us going and manage the performance."
Australia, who scraped a 14-13 victory over Argentina in Perth three weeks ago, are well aware of the Pumas' potential to notch up their first win in their second season in the elite southern hemisphere tournament.
The Wallabies are looking to extend their record against Argentina to eight consecutive victories since 2000 by doing at least as well as last year when they won by six points at Rosario Central soccer club's Gigante de Arroyito ground.
"The reality is we are fighting for the wrong end of the competition, so we have to get out there and make good things happen," McKenzie said.
"You always get something out of dealing with adversity and I'm confident we will eventually click."
Team: 15-Israel Folau, 14-Adam Ashley-Cooper, 13-Tevita Kuridrani, 12-Christian Leali'ifano, 11-Joe Tomane, 10-Quade Cooper, 9-Will Genia; 8-Ben Mowen, 7-Michael Hooper, 6-Scott Fardy, 5-James Horwill (captain), 4-Rob Simmons, 3-Ben Alexander, 2-Stephen Moore, 1-James Slipper
Replacements: 16-Saia Fainga'a, 17-Benn Robinson, 18-Sekope Kepu, 19-Sitaleki Timani, 20-Ben McCalman, 21-Nic White, 22-Matt Toomua, 23-Bernard Foley