The fast bowler picked up six for 22 as Australia, chasing a victory target of 290, were bowled out for 93, their lowest One-day score against South Africa.
''I'll never forget today, I took my 200th test wicket here and now I've taken my 200th One-day wicket at Newlands,'' Ntini told reporters after emulating the achievements of Allan Donald and Shaun Pollock.
Ntini's match figures were also the best by a South African, surpassing Donald's return of six for 23 against Kenya in Nairobi in 1996.
The 28-year-old Ntini, who started yesterday's match on 196 wickets, quit the tour to Australia earlier this year because of a leg injury and says he is ''still looking forward to getting back to 100 percent fitness''.
After going 2-0 up in the five-match series, South Africa captain Graeme Smith said he wanted the side to maintain their good form in the third game in Port Elizabeth on Sunday.
''The boys are confident but the feet are still firmly on the ground,'' said Smith after the home team eclipsed their previous best One-day victory over Australia, a 109-run win in Bloemfontein in 1996-97.
Love winning ''We know Sunday is important for the series and we want to go to Port Elizabeth and perform well.
''We love winning and we love success and we are certainly going to enjoy tonight.'' South Africa took control of the day-night match by piling up a total of 289 for seven, largely thanks to a sixth-wicket stand of 62 between Justin Kemp (51) and Pollock (38).
All rounder Pollock then conceded only nine runs in seven overs as Australia struggled with the bat.
The world champions had slumped to seven for four at one stage.
Adam Gilchrist, leading Australia in the absence of the injured Ricky Ponting, offered no excuses after his team slumped to their worst One-day defeat by South Africa.
''Justin and Shaun just took the momentum their way and it never came back to us,'' said stand-in skipper Gilchrist.
''Hats off to the way Makhaya and Shaun bowled at the start.
It was a great display of bowling and a bit of poor shot selection by us at times.
''South Africa outplayed us today.''