The Wallabies open their 2008 Tri-Nations bid against the world champions at the Subiaco Oval, with Horwill and Nathan Sharpe in a key battle with the Springboks' Victor Matfield and Bakkies Botha, a duo widely regarded as the best second row combination in the world.
With Dan Vickerman already out with an ankle injury, Horwill caused Australia some concern after suffering a knock to his sternum in training earlier this week but he has now recovered to claim his place in the starting line-up.
The 23-year-old, who made his Test debut against Fiji in Perth last year, said: "It was just a bit of a flare up of an old injury I had earlier in the year. I copped one on it but it's all good now."
South Africa defeated New Zealand in Dunedin last weekend and victory over Australia would give them a big advantage in their bid to reclaim the Tri-Nations title, but the Wallabies are eagerly awaiting the challenge.
"I'm looking forward to it," Horwill said. "They played really well last weekend and it's a big challenge for us.
"It's the first Test of the Tri-Nations for us and we are really looking forward to putting a good performance on the board."
Sharpe returns from a groin injury and Horwill is looking forward to lining up with the Western Force captain in the engine room.
"Sharpey missed the last game and he's really looking forward to playing here in Perth especially," he said.
"I'm looking forward to getting in with him and getting stuck into Victor and Bakkies.
"They are the world champions and Victor and Bakkies have played together a long time for the Bulls.
"They are two of the best going around, so we are looking forward to taking them on and hopefully can come away with a win."