With only 16 runs needed off the final 21 balls - and four wickets in hand - the hosts looked on course to complete a memorable pursuit of 458 in Johannesburg, which would have comfortably exceeded the previous record for a winning fourth-innings total of 418.
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However, the run-out of Faf du Plessis, one of two centurions together with AB de Villiers, prompted South Africa to settle for a share of the spoils.
Du Plessis, who batted for more than six and a half hours, struck 134 and De Villiers contributed 103 to a partnership of 205, a record for the fifth wicket in the fourth innings of a Test.
Yet Dale Steyn and Vernon Philander were content to block and leave following Du Plessis' exit, before the former thumped the last ball of the match for a straight six to leave South Africa eight runs short on 7-450.
The hosts started the day on 2-138 and saw Alviro Petersen depart, without addition to his overnight score of 76, to Mohammed Shami (3-107)
South Africa were four down before lunch as Jaques Kallis followed for 34.
The 38-year-old was unhappy after appearing to get an inside edge on a delivery from Zaheer Khan (1-135) - that yielded an lbw verdict and the left-armer's 300th Test wicket.
De Villiers and du Plessis came together with the score at 197-4 and responded superbly, sharing a mammoth stand to take their side to within 56 of victory.
However, De Villiers then played on facing Ishant Sharma (1-91), and JP Duminy followed before Du Plessis was ousted by Ajinkya Rahane's direct hit from mid-off.
Philander finished unbeaten on 25 off 37 balls, but there was frustration in the stands as South Africa ultimately abandoned their attempt to secure victory.
South Africa had previously completed a record one-day international chase in Johannesburg, knocking off 435 to defeat Australia in 2006.