Semenya, the defending Olympic champion and also world champion in 2009 and 2011, timed 1min 55.16sec, the fastest time of the year so far.
Burundi's Francine Niyonsaba, the Olympic silver medallist and world indoor champion, finished second in 1:55.92, with American Ajee Wilson taking bronze (1:56.65).
"I just love you guys!" Semenya said in an address to the sell-out 60,000 seater London Stadium crowd.
"It feels like home in London. I used to say Berlin was like my home. Obviously it is South Africa, but there are such fantastic people here. Beautiful."
Semenya added: "I'm lucky to have a great support team who work with me. Full credit to them. Another world title is a fantastic honour for me and I love to do it here in London.
"The crowd are so welcoming to me and it makes it feel even more special."
Semenya hinted that it would now be time to tackle the world record of 1:53.28 set by Jarmila Kratochvilova back 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."
In the race itself, Wilson went out fast, with Niyonsaba on her coattails and Semenya happy to sit back in the pack. The South African was fifth going through the bell in a fast pace of 57.98sec.
Wilson made a move with 250 metres to run, Kenya's Olympic bronze medallist Margaret Wambui immediately falling off pace.
Hitting the home straight, Wilson and Niyonsaba were neck and neck before Semenya moved smoothly outside the lead duo and motored through the line for a convincing victory.
Semenya is back in the spotlight following a study funded by the IAAF and the World Anti-Doping Agency (WADA) that showed female athletes with naturally high levels of testosterone enjoy a competitive advantage of up to 4.5 percent over their rivals.
The 26-year-old South African was one of a number of women taking medication to lower her testosterone level until 2015 when the Court of Arbitration for Sport (CAS) suspended an IAAF rule that enforced a limit on naturally occurring levels.
Semenya has studiously avoided the controversy, instead concentrating on her track performances and she won a bronze in the highly competitive 1500m on Monday in the opening race of her ambitious bid for a distance double.
Semenya, who stands to be awarded the 2012 Olympic gold medal after Russian winner Mariya Savinova was disqualified for doping, now has to await further meetings between the IAAF and CAS to discover if she again has to take testosterone suppressing medication.
