The win makes Wright the first Aboriginal woman to join an elite list of two-time winners of the prestigious $60,000 award, her earlier novel Carpentaria winning in 2007.
Even that first win was a miracle according to Wright, who said she was deeply humbled by the announcement on Thursday.
"You don't expect to win a Miles Franklin, and to do it twice is quite unbelievable," she told AAP.
It adds to a long list of accolades for Wright's "big book" that includes the Stella Prize for Australian women's writing, the Queensland Literary Award and the UK's James Tait Fiction Prize.
Praiseworthy is a sprawling tale that follows the inhabitants of a small town in Australia's north, which has been enveloped in a cloud of haze, both a manifestation of ecological catastrophe and a sign from the ancestors.
The characters' responses are rich in allegory: Cause Man Steel hatches a plan to replace Qantas with a national carrier of pack animals - Australia's five million feral donkeys.
His wife Dance becomes obsessed with butterflies and dreams of her Aboriginal-Chinese family being repatriated to China, while one son named Aboriginal Sovereignty becomes determined to suicide, and the other, Tommyhawk, dreams of being white and powerful.
Reviews have described Praiseworthy as a Ulysses of the Northern Territory, with the New York Times pronouncing it "the most ambitious and accomplished Australian novel of this century".
Wright, from the Waanyi people of the south of the Gulf of Carpentaria, explains the novel is written in an "Aboriginal chord" akin to the rhythm of women singing ceremony, with a beat that comes from the earth.
It's a big and challenging book, she acknowledges, but says novels like this are necessary as humans confront a future of global warming, inequality and displacement.
"We need to be thinking about this and planning ahead, rather than creating wars - we got a lot of work to do," she said.
It took Wright about a decade to pen Praiseworthy, and when asked about her latest win the author jokes that she is still getting over writing the novel in the first place.
"I'm in awe of it, that I had the capacity to write a book like Praiseworthy at all," she said.
She began the project at the same time as her award-winning book Tracker, and while holding the prestigious post of Boisbouvier Chair in Australian Literature at The University of Melbourne.
At times, it seemed Praiseworthy might never be finished due to other commitments, but Wright was determined to work until every page of the novel stood up.
As for all the prizes, they help ground the book within Australian literature, and encourage readers to take up the challenge of "giving the brain cells a workout", said Wright.
They also mean greater interest from overseas publishers, with Praiseworthy currently being translated into Italian.
With all this, it's no surprise to hear Wright has not made as much progress on her next two books as she might have liked - but she trusts the opportunity for deep contemplation that is necessary for her work will come once more.
"It will all become quiet again and I'll have that time to sit very quietly," she said.
