West Indies were sent into bat in Pretoria and amassed 221 for four in their 20 overs, but on an excellent batting wicket South Africa never looked in trouble in their reply and won with 15 deliveries to spare.
De Kock reached his century off 43 balls, the exact same number as when he scored a hundred against the West Indies in Pretoria in 2023 as South Africa chased down 259.
It is his ability to score all around the ground that meant no line or length was safe for the tourists, until he skied a catch off spinner Akeal Hosein going for his third six in a row.
It was perhaps more remarkable as, in typical De Kock fashion, he revealed aftert the the game he had left his bats at home by mistake and had to borrow from Dewald Brevis.
De Kock hit 10 sixes in his innings as he put on a remarkable 162 in 71 deliveries for the second wicket with fellow left-hander Ryan Rickelton (77 runs from 36 balls) that set up the win.
West Indies' total was boosted by a partnership of 126 for the second wicket between Shimron Hetmyer (75 from 42) and Brandon King (49 from 30), before the pick of the bowlers on the day, spinner Keshav Maharaj (4-22 in four overs) put the brakes on.
He removed Hetmyer, caught by Brevis at deep cover on the boundary, and bowled with excellent control.
Sherfane Rutherford, who starred on this ground for the Pretoria Capitals in SA20, smashed an unbeaten 57 from 24 balls to boost a West Indies innings that had slowed.
The third and final match in the series will be played at The Wanderers in Johannesburg on Saturday.
Both countries then head to the T20 World Cup where the West Indies start against Scotland at Eden Gardens in Kolkata on February 7, while South Africa's first match is against Canada in Ahmedabad on February 9.