South Africa requires 401 more runs for an improbable victory in the second Test after reaching 145-2 at tea on the fourth day following Australia's declaration on 331-5 on Monday.
Having been set a target of 546 after Australia added 39 runs for the loss of two wickets before declaring, South Africa batted cautiously at Kingsmead.
South Africa needs to win or draw the match to stay in the three-match series, which Australia leads 1-0.
In the middle session, the Proteas lost openers Neil McKenzie on 31 and Hashim Amla on 43. Jacques Kallis on 32 and A B de Villiers on 25 took the hosts through to tea.
Both openers were dismissed for ducks in the first innings, but Amla in particular looked a lot more assured second time around, driving seamer Andrew McDonald for three fours in the last over before lunch.
South Africa could have been in more trouble as Kallis was dropped first ball at first slip by Marcus North off Peter Siddle. The Proteas' most experienced batsman then got a grip, though, and provided some of his trademark solidity at the crease.