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 stunning innings at SuperSport Park as South Africa chased down a huge target to beat West Indies by seven wickets in the second T20I in Centurion, sealing the series with a match to spare.
Pakistan opened their T20 International series against Australia with a confident 22-run victory in the first match at the Gaddafi Stadium in Lahore on Thursday.
George Linde starred with the ball while Aiden Markram led from the front with the bat as the Proteas beat West Indies by nine wickets in the opening T20I in Paarl on Tuesday.
West Indies captain Shai Hope knows first hand about that danger that Proteas batter Dewald Brevis will pose to his team in the three-match T20I series that kicks off in Paarl on Tuesday.
