Pakistan gambled on an inexperienced pace bowling attack and were rewarded when they dismissed both South African opening batsmen early on the first day of the third and final Test at SuperSport Park on Friday.
That left South Africa on 104 for two as the sides took their first break of the day.
Rahat Ali and Ehsan Adil both claimed their first Test wickets. Rahat, playing in his second Test, dismissed Alviro Petersen leg before wicket for 10 and new cap Adil, 19, struck with his third ball in Test cricket when he had South African captain Graeme Smith caught at second slip for five.
Hashim Amla and Faf du Plessis fought back with an unbroken stand of 66. Amla was on 50 not out, reaching his half-century off 76 balls in the last over before lunch, while Du Plessis was on 29.
With Mohammad Irfan playing in his second Test, the three Pakistan pace bowlers went into the match with two caps between them.
Junaid Khan, who was impressive in the first Test, had not recovered from a thigh injury while the experienced Umar Gul's five wickets in the first two Tests were at a cost of 46.80 runs each.
South Africa were without star all-rounder Jacques Kallis because of a calf strain suffered in an optional practice on Thursday.
He was replaced by fast-medium bowler Kyle Abbott, 25, who earned his first cap after being called into the squad as cover earlier in the week.
Abbott topped the wicket-takers in the domestic first-class competition, taking 49 wickets for the Dolphins at an average of 15.36.
South Africa, who clinched the series by winning the first two Tests, had one other injury-enforced change, with Rory Kleinveldt replacing fellow fast bowler Morne Morkel.
Pakistan made three changes, with Imran Farhat replacing opening batsman Nasir Jamshed, while Rahat and Adil came in for Umar Gul and Tanvir Ahmed.