The businessman is “suffering from mental health issues”, a spokesman for his private investment company said.
Mr Packer, 50, rejoined the board of Crown in August after stepping down in 2015 as chairman and director.
The Australia-listed company thanked Mr Packer, one of the nation’s richest people, in a brief statement on Wednesday.
“We have appreciated James’ contribution to the board and respect his decision to step down from his role as director at this time,” executive chairman John Alexander said.
A spokesman for Mr Packer’s Consortium Press Holdings, Crown’s largest shareholder, said the magnate “intends to step back from all commitments”.
Earlier this month, Mr Packer sold more than A$100m ($76m; £55m) worth of Crown shares. He retains a dominant stake of about 47% in the company, which owns casinos in Australia and London.
He had only rejoined Crown’s board last year after the company exited its Macau and US investments, and switched its focus back to Australia.
It followed the jailing of 16 Crown employees in China for illegally promoting gambling.
His resignation comes after a tumultuous period for the billionaire, who was caught up in a scandal involving Israeli Prime Minister Benjamin Netanyahu last month.
Israel’s Channel 10 reported in December that Mr Packer told investigators he gave the prime minister and his wife Sara gifts.
Mr Packer’s high-profile split from singer Mariah Carey in 2016 also gained wide public attention, as did his street brawl with an Australian TV executive in 2014.
Packer is Australia’s eighth-richest person with an estimated fortune of A$4bn ($3.1bn; £2.2bn), according to Forbes. (Courtesy BBC)