Smith did not join teammates on the team bus from the hotel on Tuesday morning, instead arriving ahead of time and going to the Newlands nets behind the ground.
The 37-year-old wore a heat pack on his neck and appeared frustrated, before speaking with coach Andrew McDonald and George Bailey.
He then remained in the Australian changerooms until about 30 minutes before the toss, and did not participate in slips catching when he did come on the field.
Josh Inglis would be expected to come in for Smith, in what would have been the vice-captain's first Test at Newlands since the 2018 ball-tampering scandal.
Smith has battled neck stiffness since his first innings in Gqeberha last week, which impacted his batting in Australia's flogging at the hands of the Proteas.
He only batted against throwdowns for about 20 minutes during Australia's main session on Sunday, before a 45-minute hit on Monday.
The vice-captain also looked frustrated through the later parts of that session in Cape Town, with the series locked at 1-1 headed into the series decider.
"He is huge, one of the greatest batters we have ever had," captain Pat Cummins said on Monday.
"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."
Australia are expected to make three other changes for Newlands, with Marnus Labuschagne to hold his spot at No.3.
Scott Boland is set to be dropped with Nathan Lyon returning, while Cooper Connolly is expected to come in for Beau Webster.
Cameron Green's return has been confirmed after he overcame an abdominal strain. He will bat in the middle order, with Matt Renshaw to open.
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