Australia must win the series to take the world number one ranking from South Africa.
In a gripping finish, lion-hearted fast bowler Peter Siddle had Dale Steyn caught at mid-wicket for a duck and then bowled Rory Kleinveldt (3) with a yorker deep inside the final hour of play.
Siddle gave everything in the final over of the Test in search of the last two wickets but Morne Morkel held on.
It was the second time the South Africans had batted out for a draw in the series after denying Australia's unlikely victory push in the Brisbane opener earlier this month.
At stumps Du Plessis, who needed physio treatment for cramps late in the day, was unconquered on 110 with Morkel not out eight in South Africa's 248 for eight.
Du Plessis, who scored 78 in the first innings, reached his dogged century in his maiden Test with a cover drive for two off Ben Hilfenhaus in the hour after tea.
brief scores: Australia 550 & 267/8 dec (M Hussey 54, M Warner 41, M Clarke 38, J Pattinson 29, E Cowan 29, M Morkel 3-50) v South Africa 388 & 248/8 (F du Plessis 110 n.o., J Kallis 46, P Siddle 4-65).