The best-selling writer passed away in hospital on Norfolk Island, which lies in the remote waters off Australia's eastern coast, her publisher said in a statement.
HarperCollins Australia publishing director Shona Martyn said McCullough had overcome a string of health and eyesight problems to continue writing through dictation.
"Ever quick-witted and direct, we looked forward to her visits from Norfolk Island and the arrival of each new manuscript delivered in hard copy in custom-made maroon manuscript boxes inscribed with her name," she said.
McCullough wrote 25 novels during her career, including her first book, "Tim", which was made into a 1979 film starring Mel Gibson. The last, "Bittersweet", was published in 2013.
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She also had a fruitful scientific career, establishing the neurophysiology department at Sydney's Royal North Shore Hospital and spending decade as a researcher at Yale Medical School in the United States.
Tributes flowed in for one of Australia's most internationally acclaimed writers, who is survived by her husband Ric Robinson.
Fellow Australian author Tara Moss described McCullough as irreplaceable.
"She was fierce, funny and so supportive of other writers. Irreplaceable. RIP Colleen," she said on Twitter.