Zaheer reached the milestone with the scalp of the impressive Jacques Kallis (34) when the all-rounder was adjudged leg before wicket by Australian umpire Rod Tucker.
There was, however, a big inside edge that should have saved the veteran South African but with no referral system available in this series due to the Indian board's refusal to use technology, Kallis was unable to challenge the decision.
The controversial manner of the dismissal will mean little to Zaheer, who becomes the fourth Indian bowler to claim 300 test wickets behind Anil Kumble (619), Kapil Dev (434) and Harbhajan Singh (413).
The loss of Kallis means India need just six more wickets in two sessions to record a famous victory after Mohammed Shami had earlier bowled Alviro Petersen (76) off an inside edge as the opener failed to add to his overnight score.
Faf du Plessis (42) and AB de Villiers (25) will resume in the afternoon session focusing only on survival with all thoughts of chasing a world record target for victory firmly in the very back of their minds.
Their opinion could change, however, if the pair manage to make it through the next two hours unscathed, especially as De Villiers's natural game is to score quickly.
Shami continues to be the most impressive of the Indian bowlers, the paceman returning figures of two for 63.
He bowled Hashim Amla (four) late in the day on Saturday, while the other South African wicket to fall was that of Graeme Smith (44) who was run out.
India have never lost at the Wanderers in three previous tests played at the venue, winning by 123 runs in 2006, and playing out draws in 1992 and 1997. The second test of the two-match series starts in Durban on December 26.
(Editing by John O'Brien)
