Hashim Amla's 27th hundred came in a losing cause as Imam-ul-Haq and Mohammad Hafeez maintained Pakistan's unbeaten record in ODIs at Port Elizabeth despite a late wobble with the bat in the series opener.
Amla (108 not out from 120 balls) and debutant Rassie van der Dussen (93 from 101) shared a second-wicket stand of 155 from 170 deliveries to underpin the Proteas' 266-2 on a slow surface at St George's Park.
However, Pakistan topped that score with five balls and five wickets to spare, thanks to Imam (86) and then Mohammad Hafeez (71no), who kept his head as wickets fell around him, to make it four wins in four completed games in Port Elizabeth.
The Asian side beat South Africa by 189 runs and one run in 2002 and 2013 respectively and also defeated New Zealand by five wickets in the Mandela Trophy in 1994 when Waqar Younis was leading the attack.
Amla, who reached three figures from 113 balls with a slog-swept six off Hafeez, felt South Africa had a "good total" at the halfway point, with Van der Dussen, the top-run scorer in the Mzansi Super League, key to that.
The 29-year-old came to the crease after spinner Shadab Khan (1-41) had ended an opening stand worth 82 between Amla and Reeza Hendricks (45) and he went on to hit six fours and three sixes in his maiden knock.
Van der Dussen looked poised to become the fourth South African, after Colin Ingram, Temba Bavuma and Hendricks, to score a century in his first ODI, only to then hole out off paceman Hasan Ali (1-42).
Duanne Olivier, Pakistan's nemesis during their 3-0 defeat to South Africa in the preceding Test series, also had moments to cheer on his ODI debut, the wickets of Imam and Fakhar Zaman (25) - but he ultimately ended up on the losing side as the visitors took a 1-0 lead in the five-match series.
Part-time off-spinner Hendricks bowled Babar Azam (49) to end a second-wicket stand worth 94 and then held the catch to remove Imam after the Pakistan opener cracked Olivier to deep cover.
Shoaib Malik (12) and skipper Sarfraz Ahmed (1) then fell cheaply to ignite South Africa's hopes but Shadab (18no) proved a fine foil to Hafeez during an unbroken, match-winning partnership of 44.
Watch the second ODI, in Durban, live on Sky Sports Cricket (channel 404) from 10.55am on Tuesday.