Rabada had been in a race against the clock since hurting his hamstring in August, and had been given every chance to play in Friday's first Test in Durban.
But after the quick was limited to bowling off close to nine steps at Kingsmead on Wednesday, the Proteas opted to take the safer option on match-eve.
It means South Africa will play Marco Jansen and Anrich Nortje as their two frontline quicks, while playing two spinners in Keshav Maharaj and Simon Harmer.
Allrounder Wiaan Murder will act as a third seamer, on a Kingsmead wicket expected to turn as the game goes on.
Rabada's absence comes 10 days out from the start of the second Test in Gqeberha (formally Port Elizabeth), with the hosts hopeful he can return for that.
"We did go the conservative route, give him a couple of extra days to give him 100 per cent fitness," captain Temba Bavuma said of Rabada.
"We are confident in our medical team to get him to place we need him to be.
"As soon as he gets the green light we expect him to be within the starting line-up. We're giving him a couple of days now until the start of the second Test."
Rabada had been one of Australia's arch-nemeses on the ill-fated 2018 tour, taking 23 wickets at 19.26 in the last series between the two sides in South Africa.
He also had the infamous mid-pitch clash with Steve Smith after dismissing the then-captain, for which he was initially banned before having his charge downgraded.
South Africa are without fellow quick Lungi Ngidi for this series, who is battling his own hamstring injuries.
But Nortje's inclusion is a boost for the hosts, given he has not played a Test since March 2023.
"It's hard to ignore his X-factor. There aren't many guys around who are bowling 150km/h-plus," Bavuma said of Nortje.
"As a batter it's not something I would look forward to.
"He fits in very well to our approach from a bowling point of view, with regards to the fast bowlers."
Friday's Test at Kingsmead marks the first in the country since January 2025, and the Proteas first anywhere since a tour of India finished last November.
But they remain the world No.2-ranked side behind Australia, and are the current global Test champions after defeating Pat Cummins' side in last year's final.
Bavuma suggested Australia now find themselves in a similar position to South Africa a few years ago, with uncertainty around the tourists' best XI.
"That's probably the phase they find themselves in," Bavuma said.
"Replacing a guy like David Warner doesn't happen overnight.
"A couple of years ago we probably found ourselves in that situation."
SOUTH AFRICA LINE-UP:
Aiden Markram, Ryan Rickleton, David Bedingham, Temba Bavuma (capt), Tristan Stubbs, Wiaan Mulder, Kyle Verryenne, Marco Jansen, Keshav Maharaj, Simon Harmer, Andrich Nortje
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