Semenya defended her title in the event in 1 minute, 55.92 seconds, which is also the top mark in the world this year. American Ajee Wilson was second in 1:56.86.
Semenya is the two-time Olympic and three-time world champion in the 800. But she could be impacted in the future by a new rule that has drawn criticism.
The IAAF, track and field's international governing body, announced last month that starting on Nov. 1 it will limit entry for all international events from 400 meters through the mile to women with testosterone levels below a specified level. The IAAF maintains that women with unusually high testosterone levels have a competitive advantage over other women.
South Africa has said it may challenge the hyperandrogenism rule in the Court of Arbitration for Sport.
Semenya was asked afterward about the rule.
"I'm not going to talk about it, because I'm here to perform. To be honest, I'm just an athlete, you know? There's nothing I can do, there's nothing I can say about that," she said.
Semenya was among the sport's highest-profile athletes at the only U.S. stop on the international Diamond League series.
Ronnie Baker won the men's 100 in a wind-assisted 9.78 seconds, besting fellow American Christian Coleman in breezy but sunny conditions at historic Hayward Field.
Coleman, who holds the world record in the 60, won both the 100 and 200 last year at the NCAA championships in Eugene and claimed the silver medal in the even at last year's world championship. He was making his outdoor debut in the Pre.
"It was alright. It was just my first race getting back. Haven't had many hard days of practice," he said. "I felt pretty good. It was my season opener so (I'll) take it from there and get better."
Justin Gatlin had been scheduled to run in the 100 on the men's side but withdrew earlier this week because of hamstring tightness.
On the women's side, a pair of Ivory Coast athletes topped the podium in the 100. Marie-Josee Ta Lou was first in 10.88, followed by Murielle Ahoure in 10.90. The loaded field included reigning world champion Tori Bowie and the 2016 Olympic gold medalist Elaine Thompson.
American Noah Lyles won the 200 in 19.69, a personal best and the fastest time in the world this year.
"Finishing is my strong suit, so when I came off and saw I was ahead of the pack I was really excited, and I knew this was gonna be a fast time," Lyles said.
Shaunae Miller-Uibo of the Bahamas won the 400 in 49.52. Organizers announced on Friday that Allyson Felix had withdrawn from the race for undisclosed reasons.
American Shelby Houlihan ran a personal best 3:59.06 in the 1,500, while Jamaica's Janieve Russell won the 400 hurdles in 54.06. Jenn Suhr, the American record holder in the outdoor pole vault, won the event at the Pre with a meet-record leap of 15 feet, 11 inches.
Christian Taylor won the men's triple jump (58-2), Qatar's Mutaz Essa Barshim won the high jump (7-8¾) and Ryan Crouser won the shot put with a meet record throw of 73-11.
Kenyan Timothy Cheruiyot won the final event of the day, the Bowerman mile, in 3:49.87. The announced crowd at the event was 12,667.
Semenya, 27, said the 800 world record was the goal, "maybe this year." The record is 1:53.28, set in 1983 by Jarmila Kratochovilova of Czechoslovakia. Semenya's best time in the event is 1:55.16.
She was asked after the Pre what motivates her.
"When you live, you gain experience, I'm more mature. I've been in this world for almost three decades now. Obviously I'm a sports science student, I've learned about everything, especially in sports. ... I just want to inspire people, and inspire the youth, to show them that if you believe, anything was possible," she said.
When the IAAF's decision was announced, the South African Olympic body's president said it was "disappointed by the IAAF ruling, and especially given that Caster's name is again being dragged through the publicity mill."
"We are concerned that the decisions have been approved without taking into account all factors," Gideon Sam said, adding that athletes' "dignity and human rights are at the top of the agenda."
The IAAF maintained there was "broad medical and scientific consensus, supported by peer-reviewed data and evidence" to back its position.
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