The triumph, achieved with nine balls to spare, secured a 2-1 series result - the first time in 12 years that West Indies Women have won a bilateral series against South Africa.
Chasing 148 for victory, West Indies were anchored by a superb innings from captain Hayley Matthews, who struck 65 off 50 deliveries, including nine fours and a six.
She shared an 82-run third-wicket partnership with Shemaine Campbelle, who contributed a composed 42 off 38 balls.
Despite early wickets falling to Qiana Joseph and Realianna Grimmond, the hosts kept their chase on course.
Chinelle Henry delivered the finishing touches in style, smashing an unbeaten 20 off 11 balls - including a 4, 6, 4 sequence from the first three balls of the penultimate over - to seal the win.
Matthews, named both Player of the Match and Player of the Series, ended the series with back-to-back half-centuries and proved decisive throughout.
Earlier, South Africa opted to bat first after winning the toss. They posted 147/6, thanks largely to a maiden T20I half-century from 20-year-old Miane Smit of Bloemfontein, who hit seven fours and a six in an unbeaten knock. Skipper Laura Wolvaardt added 28 off 24, while Tazmin Brits chipped in with 20.
The T20I series win meant the two white-ball series on tour were shared, with South Africa having previously clinched the WODI series 2-1.
Former South Africa captain Dane van Niekerk has been named in the extended Proteas Women's training squad ahead of the Women's Cricket World Cup, as the team prepares for a critical tour of Pakistan and the global showpiece in India and Sri Lanka.
South African all-rounder Corbin Bosch has found himself in hot water for his innocuous gesture during the second T20I against Australia in Darwin on Tuesday.
Jason Holder delivered a match-winning performance with both bat and ball as West Indies edged Pakistan in a thrilling two-wicket win on Saturday, levelling the three-match T20I series in Lauderhill, Florida.
Pakistan and West Indies are set to clash in a three-match T20I series at Central Broward Park & Broward County Stadium, marking the eighth bilateral T20I series between the two sides.
