Tobias died in a Johannesburg hospital after a long illness, according to South Africa's University of the Witwatersrand, where he chaired the anatomy department from 1959 to 1990.
He "was one of the greats in human evolutionary studies," Nick Barton, director of Oxford University's Institute of Archaeology, told the Associated Press.
When Tobias turned 80 in 2005, he wrote of a life enriched by "coincidence, synchronism, eureka moments."
"You go to search for something — an odd tree — and you find something else, something that may prove to be even more important than that which you had set out to examine! This is the essence of serendipity," he wrote, describing a 1945 visit to a cave in Limpopo to see a twisted yellowwood tree when he was 20.
Kneeling in the sandy soil to get a better look at the tree, he felt something hard and pulled out an ancient stone tool.
He launched an archaeological dig in the cave, which he later named Mwulu's Cave. It became a significant site, casting light on the earliest artistic activity by predecessors of humans. Some 3,000 stone tools were excavated from the site.
Nominated three times for a Nobel Prize, Tobias was one of the University of Witwatersrand's preeminent scientists. He was initially drawn to genetics after his sister, Valerie, died because of diabetes. He earned five degrees, including in the fields of medicine, genetics and paleoanthropology.
Tobias was involved in the excavation of the Sterkfontein Caves, northwest of Johannesburg, one of South Africa's most important fossil sites and a place where numerous hominid fossils have been found. He was also part of the research on hominids in the Olduvai Gorge in Tanzania, collaborating with British archaeologist Louis Leakey on the identification of one the early hominids, Homo habilis, in 1964.
Earlier, Tobias had been one of the scientists in 1953 who exposed the 1912 Piltdown Man as a hoax, explaining that an orangutan's lower jawbone had been buried in England with a human skull and passed off as a specimen of ancient man.
In 1995, Tobias announced the discovery of Little Foot, an almost complete hominid skeleton unearthed at Sterkfontein by a team he led.
Although he had no immediate survivors, he was proud of the legacy he left behind at the University of Witwatersrand: "I am married to my work, the medical school and the anatomy department at Wits. I also have a large family of around 10,000 children — my students," he said in a 2010 interview.
In a Twitter message, Derek Hanekom, South Africa's deputy minister for science and technology called Tobias "a brilliant man, a visionary, a pioneer, a legend!"
Born in Durban, South Africa, on Oct. 14, 1925, Tobias was reading by age 3.
Of his own intellect, he said in a 2005 interview: "The genes lay down a range of possibilities, but your environment, your teaching, your education select among those possibilities."
He was an outspoken critic of apartheid who occasionally was warned by South African authorities that his research grants might be withdrawn if he failed to toe the line. "But I felt it was my duty to speak out on the meaning of race, and did so on every possible occasion," he said in 2005.
Above all, Tobias celebrated people.
"People are fun. I love dinner parties and braaivleis [barbecues] and camping out with my students at Sterkfontein and Makapansgat and sing-songs around the campfire," he said. "Part of me is quite an ordinary sort of chap. I love quite simple things."