Van Wyk, who is on the Proteas’ stand-by list for next month's 50-World Cup should wicketkeeper Quinton de Kock not recover from injury, smashed 114 from 70 balls with nine fours and seven sixes to help the home side score 195 for three.
West Indies made a bright start but lost wickets at regular intervals with only opener Lendl Simmons (49 from 31 balls) offering prolonged resistance as they collapsed to 126 all out in 19 overs.
All-rounder Wiese was the pick of the South African bowlers for the second match running with career-best five for 23 in his four overs, the second best bowling figures in Twenty20 internationals for the Proteas.
After being sent in to bat, Van Wyk and Reeza Hendricks put on 111 for the first wicket before the latter was out for 42.
The 35-year-old Van Wyk reached his hundred from 67 balls, his first in Twenty20 internationals.
West Indies won the three match 20-over series 2-1. The first of five one-day internationals will be played in Durban on Friday.
(Reporting by Nick Said in Cape Town, editing by Ed Osmond)
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