De Kock hit a career-best 115 off 49 balls on Thursday at SuperSport Park. Ryan Rickelton finished the rout with a career-best 77 not out off 36.
The left-handers battered West Indies for 162 runs in 11.5 overs.
"Special to watch," South Africa captain Aiden Markram said.
"Quinny put on a great show for the crowd. Ricks flies under the radar but to get us home back to back is a good effort from him."
West Indies made a hefty 4-221 in Centurion but the hosts cruised to 3-225 with 15 balls to spare.
The target didn't faze the Proteas. They chased down 258 against the same opposition on the same ground in 2023, led by de Kock's 100, his only previous T20 century.
After losing five straight bilateral T20 series, South Africa gave coach Shukri Conrad his first T20 series win as they clinched it 2-0 with a match to spare. That third game is on Saturday, then both teams head to the T20 World Cup starting next week in India and Sri Lanka.
De Kock was rested from the first T20, where Markram hit 86 not out in a nine-wicket win chasing 174. The captain made only 15 this time but de Kock took up the mantle, launching sixes against five of the six West Indies bowlers.
He brought 50 up in 21 balls and got to 100 off 43. He was going for a third consecutive six off Akeal Hosein when he miscued to mid-off and was out after smashing 10 sixes and six boundaries.
Earlier, spinner Keshav Maharaj was the pick of the South Africa bowlers with 2-22.
Shimron Hetmyer top-scored for West Indies, two days after hitting 48 in Paarl, with a 42-ball 75, 50 of them from boundaries.
Hetmyer's 126-run partnership with Brandon King, who was caught on the boundary on a 30-ball 49, left them 2-133 after 12 overs.
Sherfane Rutherford then blasted 57 in an unbroken stand of 76 with Romario Shepherd, who made 17.
41°C