The experienced duo will pull on the Wallabies jersey for the last time on home soil before embarking on their World Cup swansong later this year.
And coach John Connolly paid tribute to the pair, claiming they are 'virtually icons of Australian sport' after including the duo to face the Springboks in the Tri-Nations.
"We've just been so blessed in this country to have such incredibly consistent players playing in two of our key positions over the past 12 or so years," he said.
"They are two great warriors of Australian sport and I'm sure they will receive a fitting farewell from the supporters on Saturday night in what is such a crucial Test for the Wallabies."
Gregan is a veteran of 132 Tests, while Larkham will make his 100th appearance for his country - becoming just the third man behind his long-time halves counterpart and legend David Campese (101 Tests) to register a century of caps for Australia.
Mark Gerrard has been named on the right wing in place of the suspended Lote Tuqiri, who was banned for two matches after he failed to show up for a recovery session and team medical earlier this week.