De Villiers, who struck the fastest ODI ton in history off 31 balls in Friday???s second match, watched on as Hashim Amla (61no) and Faf du Plessis (51no) steered South Africa to their target off 24.1 overs, to put their team in an unassailable position in the five-match series.
West Indies batted in hapless fashion after skipper Jason Holder (17no) won the toss, only Marlon Samuels (26) scoring over 20 on a good pitch.
The tourists were in the mire once Vernon Philander (3-27) claimed the wickets of openers Dwayne Smith and Chris Gayle for single figures, both caught behind by wicketkeeper De Villiers.
Fast bowler Dale Steyn (2-21) followed up with the wickets of Narsingh Deonarine and Denesh Ramdin as the West Indies stumbled to 43-4 off 12.3 overs.
Samuels offered a measure of resistance before he attempted to take the attack to leg-spinner Imran Tahir and only succeeded in picking out Rilee Rossouw in the deep.
Tahir went on to claim career-best ODI figures of 4-28 after Andre Russell was clean bowled by Morne Morkel, heaving across the line.
The slow bowler won lbw decisions against Jonathan Carter and Carlos Braithwaite, before last man Sulieman Benn (18) was stumped by a distance following Jerome Taylor???s second-ball duck.
South Africa lost Rossouw early in their reply for seven when the opener miscued an attempted pull off Holder to mid-off but thereafter the Windies??? hopes of further breakthroughs were thwarted by Amla and Du Plessis.
The pair combined to put on a 50-run partnership off 76 balls before Amla posted his 27th one-day international fifty off 55 deliveries.
Du Plessis reached his own half-century, his 12th in ODIs, off 69 balls with South Africa needing just four runs to win ??? Amla completing the job by pulling Gayle behind square for four.