Pakistan won the toss and chose to field first, making light work of their visitors’ top order as they bowled them out for 110 in 19.2 overs.
It never looked enough and the home side romped to victory with 41 balls to spare ahead of Saturday’s third and final fixture at the same venue.
Babar Azam was not out with 11 from 18 deliveries and became the highest run-scorer in T20 Internationals with 4,234, going beyond India's Rohit Sharma.
Six of the South African batters were bowled as Pakistan found prodigious seam off the wicket, with only Dewald Brevis managing an innings of any substance with 25 from 16 deliveries.
There was a cavalier nature to the batting too with no-one in the visitors' line-up able to dig in and lay a platform.
Fast bowler Salman Mirza took 3-14 in his four overs.
South Africa could not find the same assistance from the wicket and Pakistan raced to victory on the back of Saim’s fine knock.
Sahibzada Farhan, 28 from 23 balls, was the only Pakistan batsman who was dismissed after he was trapped leg before wicket by Corbin Bosch.