After captain Matthew Breetzke had won the toss and opted to bat, the tourists were given a good start when openers Lhuan-dre Pretorius and Quinton de Kock put on 72 in 14 overs.
The introduction of spin into the bowling attack was when the wheels started to fall off for the visitors as Salman Agha (2-18) had Pretorius caught at long-off for 39.
Agha then got his second wicket when Tony de Zorzi chipped one straight to cover while De Kock fell to left-arm spinner Mohammad Nawaz (2-31) for 53 off 70 balls to leave the Proteas on 106-3.
Abrar Ahmed then sliced through the visiting batting line-up to finish with figures of 4-27 as the Proteas were bowled out for just 143 in the 38th over.
Nandre Burger gave the visitors hope with the wicket of Fakhar Zaman for a duck with the second ball of the innings but Saim Ayub and Babar Azam settled Pakistan nerves with a second-wicket partnership of 65.
Babar was run-out for 27 but Ayub was joined by Mohammad Rizwan and the pair added another 65 runs to take the hosts close to victory.
Ayub lost his wicket for 77 but it mattered little as Rizwan was 32 not out as Pakistan reached their 144-run target in the 26th over.
Quinton de Kock produced a batting masterclass as South Africa crushed Pakistan by eight wickets in the second ODI in Faisalabad, chasing down 270 with nearly 10 overs to spare to level the three-match series 1-1.
The Proteas fought to the bitter end but ultimately fell to a two-wicket defeat with two balls to spare against Pakistan in the first ODI in Faisalabad on Tuesday.
Dewald Brevis has been ruled out of the Proteas' three-match ODI series in Pakistan, that starts in Faisalabad on Tuesday, after suffering a low-grade shoulder muscle strain.
Pakistan cruised to a four-wicket victory against South Africa in the third T20 International at the Gaddafi Stadium on Saturday to claim the series 2-1.
