Pakistan have an unassailable 2-0 lead ahead of the third and final fixture in Johannesburg on Sunday.
South Africa surprisingly sent the visitors in to bat on a ground where it is known to be difficult to chase under lights, and Pakistan posted an above-par 329 all out on Thursday.
Heinrich Klaasen provided the only real resistance for South Africa with an excellent 97 from 74 balls but was the last man out as they were dismissed for 248 in 43.1 overs, having been outplayed in all facets of the game.
Captain Mohammad Rizwan scored 80 from 82 balls to anchor the Pakistan innings, but the impetus for their total came from a superb 63 from 32 deliveries by Kamran Ghulam.
Babar Azam provided 73 in 95 deliveries with the visitors profiting from some sloppy South African fielding as they dropped numerous catches and were not accurate enough with the ball.
Debutant fast bowler Kwena Maphaka, 18, returned figures of 4-72 in his 10 overs, the pick of a disappointing bowling effort from South Africa.
Several of the home side's batters got starts but Pakistan picked up wickets at regular intervals and Klaasen ran out of partners in the chase.
Afridi showed superb control and recorded figures of 4-47 as he ripped through the South African middle-order, removing the dangerous David Miller for 29 to take the game away from the home side.
