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The Olympic champion's time of one minute, 55.16 seconds was a personal best and a world leading time for 2017.
Francine Niyonsaba of Burindi took silver and Ajee Wilson bronze for the United States, both blown away by Semenya's astonishing acceleration in the final 50 metres.
Britain's Lynsey Sharp, 27, was eighth.
She told BBC Sport: "Obviously that is the worst result I could have had. I committed from the first lap, I didn't just want to go through the motions. But I didn't have the legs with 250m to go.
"It's been hard to get to this point, so I'm proud of that."
Semenya, 26, said she next plans to beat the 800m world record of one minute, 53.28 seconds, set by Jarmila Kratochvilova of the former Czechoslovakia in 1983.
"We need to clear 1:55 first and it will require a lot of hard training," she said.
"I have Olympic, world and Commonwealth titles now so maybe it is time to target the world record. It's the next thing on the list. I know it will be difficult but I will have to attempt soon, maybe."
Analysis
Paula Radcliffe, 2005 marathon world champion
Caster Semenya is unbeatable. She just strode out there - she waited and waited so patiently and struck at the right moment.
Lynsey Sharp was in a good position but the pace was just wound up.
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South Africa's Caster Semenya won the women's 800m in imperious style as she cruised to gold on the closing night of the World Championships in London.