Sayers, 30, has been on the cusp of Test selection for several years off the back of consistent JLT Sheffield Shield performances for South Australia.
The right-arm seamer claimed 62 wickets in the 2016-17 summer to be named Shield Player of the Year and added another 17 scalps from just five matches this season.
Sayers will be Australia’s 452nd men’s Test cricketer and was presented his Baggy Green cap by former Test batsman Adam Voges before play in Johannesburg.
He replaces Australian lead paceman Mitchell Starc, who has been battling a toe injury.
Queensland duo Matthew Renshaw and Joe Burns have also been included as part of a new-look Australian lineup for the fourth and final Test against the Proteas.
Batsman Peter Hansdcomb rounds out the additions for the tourists with Starc and suspended trio Steve Smith, David Warner and Cameron Bancroft the omissions.