Independent Kerryn Phelps has ended over a century of Liberal dominance in the Sydney seat of Wentworth, forcing Scott Morrison into minority government, the ABC predicts.
ABC election analyst Antony Green has called it for independent Kerryn Phelps.
"They certainly have some strong views and they've shown them tonight", he said.
Despite losing his fragile one-seat majority, the Liberal leader pledged to get his government back to work in parliament on Monday.
Mr Sharma congratulated Dr Phelps and described her as "formidable".
With around half the vote counted, official results from the Electoral Commission showed Liberal candidate Dave Sharma had attracted just 39 per cent of first-preference votes.
It is understood that Mr Sharma is not interested in a Senate seat, and the only one available to him would be the spot promised to Andrew Bragg, who pulled out of the preselection race because he felt a female candidate was the Liberal's best hope in Wentworth.
Independent candidate Kerryn Phelps delivers her victory speech at a Wentworth by-election evening function at North Bondi Life Saving Club in Sydney, Saturday, Oct. 20, 2018.
"This win tonight should signal a return of decency, integrity and humanity to the Australian Government."
"Thank you to the people of Wentworth for placing your trust in me", she said.
The seat became vacated by former Primer Minister Malcolm Turnbull following the dramatic leadership spill in August.
"We have paid a great price for the events of a few months ago", Mr Morrison said, referring to the former Wentworth member Malcolm Turnbull being deposed as prime minister after a bloody internal coup.
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Mr Sharma's campaign was derailed in the past two weeks due to a series of blunders and problems in Canberra.
"But as a party, we will continue to rise again". "And let's hope for a bit of common-sense on climate action", she said.
"It is obviously a devastating night for the Liberal Party", Mr Zimmerman said.
Labor's Deputy Leader Tanya Plibersek said the swing against the Government was significant.
Morrison said that while the loss was not unexpected given indications from opinion polls, his party had received a loud message from voters.
Mr Sharma, a former ambassador to Israel who endured a bitter preselection battle in order to contest Wentworth, addressed the crowd after being welcomed with chants of support.
"I don't think anyone can be confident - we don't really know how this is going to turn out", the local GP said.
"This is the beginning of the end of the Morrison Government", he said.
"A great day for Australian democracy".
Mr Turnbull's son Alex, who had been a vocal critic of the Liberal Party during the campaign and a thorn in the side of its strategists, said the result was "incredible".
Mr Morrison previously appealed to voters not to opt for an independent because it would jeopardise the Government's one-seat majority in the lower house, potentially making it hard to pass legislation.