Towering Pakistan seam bowler Mohammad Irfan took two wickets with the first two balls of the match as South Africa struggled to 9-234 in its 50 overs in the fourth one-day international on Thursday.
Irfan removed top-ranked ODI batsman Hashim Amla and then Colin Ingram for first-ball ducks to leave South Africa on 2-0 after two deliveries at Kingsmead.
AB de Villiers (75) and David Miller (67) shared a century stand to lift the home team.
But Irfan, Junaid Khan and spinner Saeed Ajmal struck regularly in taking three wickets each to keep the Proteas to a low score in a game the Pakistanis must win to keep the series alive.
The 216cm Irfan finished with 3-46 as South Africa lost 5-81 when the De Villiers-Miller stand was broken.