In a wide-ranging speech at the Lowy Institute on Friday, Penny Wong argued ignoring a multicultural society would cause Australia irreparable damage.
She said going down the path of a monoculture would damage hard-fought diplomatic gains.
"The call for a monoculture is a call for Australia to curtail our choices and cut off our connection, to look inwards, to have no friends to work with," Senator Wong said.
"There is a lot of damage that can be done, because Australians would be turned against each other. Australia would be a more hostile place.
"At a time where external and internal forces are seeking to divide us, turning Australians against each other makes us more vulnerable."
The comments took aim at the policies of One Nation, whose leader Pauline Hanson called for a monoculture in a speech to the National Press Club in June.
While One Nation and Senator Hanson were not named in Senator Wong's speech, she used the address to highlight criticisms of the minor party's approach.
"Division makes us easier to exploit; it doesn't make us stronger," she said.
"Turning Australians against each other is the opposite of patriotism. Our resilience starts with how we choose to live together."
Multiculturalism remained one of Australia's greatest strengths, Prime Minister Anthony Albanese said.
"We can be a microcosm ... living side by side, people of different backgrounds, overwhelmingly in harmony," he told reporters in Canberra.
"My government will not do anything that breaches harmony. What we want is for Australia to be more united.
"It is other forces that seek to divide people for political ends."
Senator Wong said the push for multiculturalism was critical at a time of rising social divisions.
"It has been one of our country's greatest strengths and ... we are still going through a difficult time, but it is something all of us contribute to," she said.
"We live in a time where social media and the fermenting of anger and division is kind of the way so much is dealt with.
"We just have to keep pushing back against that because, ultimately, I do think it makes us weaker."
Senator Wong said partnerships with neighbouring countries, particularly in the Pacific and Southeast Asia, were valuable in a time of global disruption.
Relations with Asia helped secure fuel during oil shortages, while Pacific alliances, such as the Ocean of Peace agreement signed with Fiji in July, would help provide stability.
"Denigrating our region and neglecting our partners is no way to secure Australia's interests - neither is encouraging some kind of retreat from the world and the institutions that go with it," Senator Wong said.
"I've always believed the ability of Australians to connect with people from every part of the world is a national asset."
Senator Hanson has come under fire for failing to name the leaders of crucial allies.
In an interview with News24, the One Nation leader said diplomacy with Southeast Asia would be "no problem", despite her previous comments about Asian countries.
Asked in the interview if she could name the president of Indonesia or the prime minister of Japan, two crucial allies of Australia, Senator Hanson said she did not know.
She did, however, know the president of China was Xi Jinping.
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