In a see-saw battle, South Africa looked set to create history by chasing down the highest fourth-innings total ever when du Plessis (134) and de Villiers (103) were going great guns.
However, India hit back with quick wickets towards the end of the day, and both teams eventually settled for a draw.
The day began with India looking all set to go 1-0 in the two-match series, needing eight wickets to win on the final day at the Wanderers. But, after losing Alviro Petersen (76) and Jacques Kallis (34), du Plessis and de Villiers played incredible knocks to actually put the Proteas in a great position to go for a record win.
The pair of du Plessis and de Villiers added 205 for the fifth wicket to put the hosts in command. But, just when it looked that South Africa would canter to victory, de Villiers was clean bowled by Ishant Sharma as he chopped one on to the stumps. South Africa were still in with a decent chase of chasing down the target since in-form Vernon Philander gave good support to du Plessis.
The Proteas eventually gave up hopes of winning when du Plessis was brilliantly run-out by Ajinkya Rahane. du Plessis' marathon knock lasted for 395 minutes, and his crucial dismissal ensured that India maintained their unbeaten run at Johannesburg.