Tributes are flowing for the 46-year-old who has died in Darwin.
He'd suffered years of ill health, having contracted Hepatitis B as a child, leaving him with liver and kidney disease.
Born blind, Dr Yunupingu first picked up a guitar at the age of six, learning to play it upside down because he was left handed.
His unique voice spawned a career that saw him sell more than half a million albums, recorded in his native Yolngu tongue, and perform for audiences that included the Queen and former US President Barack Obama.
Friend Vaughan Williams took the artist to hospital last week, amid concerns he may not have been receiving renal treatment. He died in the Royal Darwin Hospital on Tuesday afternoon.
"He was a musical genius who could do rock, gospel, soul. He could do it all," Mr Williams has told the ABC, saying his death was all the more crushing because he felt it was "preventable".
"I feel he was trapped in the same cycle of bad health that so many Indigenous people are trapped in," he said.
"His high tenor voice and aura-like persona create emotion, compassion and a feeling of peacefulness and longing with audiences in Australia and around the world"
Prominent Australians have offered tributes, including Greens Senator Sarah Hanson-Young who tweeted: "A true musical genius. A stark reminder why we must close the gap of life expectancy for Indigenous ppl."
Midnight Oil frontman and former federal government minister Peter Garrett also took to Twitter to mourn the loss.
"My dear friend Dr Yunupingu - a truly great musician - is gone," he posted.
"Very sad news. Too young, so much left to give. Heart goes out to family."
Dr Yunupingu's soulful and emotive voice came to the fore in 2008 with the release of his debut album, which peaked at No.3 on the ARIA charts and went triple platinum.
Sydney Morning Herald critic Bruce Elder has described him as possessing "the greatest voice this continent has ever recorded".
In 2012 he was forced to cancel a number of European performances due to illness, including performing at the London Olympic Games. He had found substantial success there, with his debut album hitting the top 10 in both
Switzerland and Germany.
Prior to his solo success Dr Yunupingu had been a member of the legendary Indigenous band Yothu Yindi, fronted by his late uncle M Yunupingu, who was named Australian of the Year for 1992.
He followed in his uncle's footsteps, being named the Northern Territory's Australian of the Year in 2009.
Former prime minister Kevin Rudd said Australia had lost "a good man, the son of a great people and a voice which could evoke an extraordinary magic".
His publicist posted a statement on Facebook describing him as a "great Australian".
"Dr G Yunupingu is remembered today as one of the most important figures in Australian music history, blind from birth and emerging from the remote Galiwin'ku community on Elcho Island off the coast of Arnhem Land to sell over half a million copies of his albums across the world, singing in his native Yolngu language," the statement read.
"The highest selling Indigenous artist in history, Dr G Yunupingu released two subsequent top five studio albums Rrakala and The Gospel Album, achieved a swag of ARIA Awards, performed across the globe for audiences including Queen Elizabeth II and Barack Obama and released the first Indigenous language single to reach the top five, all the while continuing to call Elcho Island home."
His legion of fans are also mourning the singer's loss.
"Grace Dr.G.Yunupingu. We're a little bit heartbroken. We've put our kids to bed to the backdrop of his music since they were tiny. Just astoundingly beautiful," Victorian woman Natalie Dillon wrote on Facebook.
A documentary about Dr Yunupingu's life is scheduled to premiere next month at the Melbourne Film Festival.
In line with Indigenous tradition the full name and images of the late artist are not being published.
His family is expected to be offered a state funeral, News Corp reported.
