Horwill suffered a minor hamstring injury at training on Tuesday and will miss the Suncorp Stadium clash, as well as the game against Argentina in Perth later this month.
Scrum-half Will Genia has been given the captaincy in Horwill's absence, with Kane Douglas taking his place in the second row, and Kepu is confident the players can step up.
"Losing your captain's always a massive blow to any team but, in saying that, Will Genia is a great captain himself," said Kepu.
"He's led Queensland and the Wallabies and not to mention Ben Mowen, who's transitioned well into that vice-captain role.
"Nothing's really changed, Ben Mowen runs the line-outs pretty much and he's always talking among the forwards and Willie's out among the backs.
"We've got good guys there that can fill those shoes and Kane gets an opportunity this week to showcase what he has and I'm sure he'll do a good job."
The Wallabies have several key forwards missing and were overpowered by the New Zealand pack in the opening two defeats of the Rugby Championship campaign.
But Kepu is confident the forwards can nullify the Springbok pack and supply quality ball for their backs.
"Every team has their pros and cons and we'll be working on perfecting our strengths and working on them and trying to execute to the best of our ability," he said.
"You can't shy away from it, the Boks have got a big pack and we'll be doing our best to counteract that.
"You do lose players (to injury) but that's sport and that's what it's all about, and guys get the opportunity and guys make the most of it.
"It's all about making the most of your opportunity, and we've got a pretty hungry pack to get back on track and get some more wins on the board."
Israel Folau will start at full-back for the first time for Australia and Springboks skipper Jean de Villiers is aiming to target his inexperience.
The former rugby league man has started his first four internationals on the wing and De Villiers, despite being wary of a talented Australia back-line, is hoping to capitalise on any nerves.
"Obviously he's not the perfect player yet maybe, but he's still learning the game I think in a way and we'll try to expose that, so we've got our plans that have been made for this one," he said.
"He's obviously great under the high ball. He really contests well and obviously with the league and AFL background, you can see that he's really good at that.
"With that he's got fantastic pace, he's such a balanced runner and a great player. It's good to have a guy like that in rugby union, he's obviously a big threat for us and he seems like he's enjoying union.
"Yeah he's a classy player but then again if you have guys like (Quade) Cooper, Adam Ashley-Cooper, who's been so consistent over the last number of years, (Christian) Lealiifano is really settling into the number 12 shirt, it makes for a well balanced back-line.
"And obviously (Will) Genia at nine is a world-class player, so we'll be challenged in that regard."
Australia are the only team in the tournament without a point after Argentina claimed a bonus point against the Springboks, with the Pumas facing New Zealand in Saturday's other game.