Australia will wait until Tuesday's toss before confirming their side for the series decider, which captain Pat Cummins had compared to having a "grand final" feel.
But Matt Renshaw is expected to open with Nic Maddinson left out, while Cameron Green is fit again and will bat in the middle order.
Marnus Labuschagne is set to hold his spot ahead of Josh Inglis after a frustrating run of starts, leaving selectors to decide between Cooper Connolly or Beau Webster at No.7.
Connolly has every chance of coming in, after a series of disappointing returns for Webster.
A squeeze also looms with the bowlers, with Nathan Lyon likely to play a role and Scott Boland at risk of being forced out despite his five-wicket haul in Gqeberha.
But part of that is likely to hinge on Smith and his sore neck, after it troubled him last week.
The vice-captain only faced gentle throwdown for around 20 minutes on Sunday, but had a much longer stint wearing a helmet on Monday.
He batted for around 35 minutes as batting coach Michael Di Venuto threw balls with the side-arm device, before a lengthy break as Smith stretched his neck.
The 37-year-old then returned for about 10 minutes, before ending his session. Australia had been confident even before that on Monday he could play.Smith has had a frustrating tour of South Africa, with three scores in 20s.
He looked good without a big score in Durban, before appearing in nice touch in the first innings in Gqeberha until the neck issue became apparent.
"He has been batting really well. Even in that first Test, that first innings, I thought he looked in total control until he found the outside edge on one ball," Cummins said.
"He is huge. One of the greatest batters we have ever had.
"You don't play 100 odd Test matches without playing Test matches where you're not 100 per cent fit.
"Even though he is probably not going to be 100 per cent hopefully he can compartmentalise that, like he has done 100 times before with other things, and come out and contribute like he does every week."
All eyes will no doubt be on Smith in Cape Town, in he and Australia's first Test back at the venue since the 2018 ball-tampering scandal.
The venue has changed somewhat since then, including the away changerooms where the plot for Cameron Bancroft to use sandpaper was allegedly hatched.
Sold-out crowds are expected across the first three days, while the cricket store in the ground has had sandpaper available as banter for Australian visitors.
Even before 2018, Newlands has a storied history with Australia. They were bowled out 47 at the ground in 2011, and clinched a series at the same venue in 2014.
"Really, we haven't spoken about it too much this week," Cummins said.
"We've probably got a few reasons not to enjoy this venue, but every time we come here, it's always, 'Wow. What an amazing cricket ground.'
"I've played here a few times over the years and this is where I played my T20 debut, so I feel like a lot of the times when I travel around South Africa it's my debut tour that brings back a lot of memories, rather than the 2018 tour."
Beyond the series, Australia will give up the No.1 spot in the world rankings to South Africa if they are beaten at Newlands.
"It feels like the climax of a huge series. It felt inevitable it was going to be 1-1," Cummins said.
"The cricket has spoke for itself ... both teams have fired shots.
"In terms of Tests, it's (six weeks) until our next Test. So this is your grand final that you put everything into."
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