Semenya is favourite to win the 800 metres women's gold medal in the first Games hosted by South America after clocking the fastest time this year, 1 minute 56.64 seconds.
Having won the 2009 world championship 800m title in Berlin, the South African had to undergo gender testing before being permitted to compete as a woman. The 2012 London Olympics 800m silver medallist has made a timely return to form this year after several injury-plagued seasons.
World men's 400m champion Van Niekerk, whose coach is a grandmother from central city Bloemfontein, seems the next best South African prospect for track and field gold. Three-time African discus champion Vincent Hogan misses out on Rio, though, having tested positive for methylhexaneamine at the national championships last April.
Chad le Clos, who stunned American multi-Olympics gold medallist Michael Phelps by winning the London Games 200m butterfly, is widely regarded as the best hope for swimming success. The star from Indian Ocean city Durban revealed this week that both his parents are battling cancer, but they plan to cheer him on in Brazil.
Jaco van Zyl and Branden Stone will represent South Africa in golf after Major winners Louis Oosthuizen and Charl Schwartzel and Branden Grace said they were unavailable.
All cited Zika, a mosquito-borne virus which has reportedly infected about 1.5 million Brazilians since last year, for withdrawing. The national men's and women's football teams have qualified for Rio, although neither squad are realistic medal contenders.
But the men's sevens rugby squad, who have overlooked veteran Springbok winger Bryan Habana, are among the chief candidates for gold in a 12-team field. South African medal winners in Rio will not only achieve sporting fame, but also be rewarded financially.
Gold medallists will become 500,000 rand ($35,000, 32,000 euros) richer, silver medallists 250,000 rand better off and bronze medallists receive a 100,000 rand boost to their bank balance.