Jeremy Hunt has compared the EU to the "prison" of the Soviet Union as it tries to prevent member states from leaving.
In a notable speech at the Conservative Party Conference in Birmingham, the foreign secretary warned Brussels against rejecting the "hand of friendship" offered by Theresa May.
He also used his address on Sunday to call for unity within the Tory party, with Mr Hunt cautioning continued Tory division could risk the "wrong Brexit, a Corbyn Brexit or perhaps no Brexit at all".
Despite backing Remain at the 2016 EU referendum, Mr Hunt has since stated he would now vote Leave due to the "arrogance" of the EU during divorce negotiations.
Increasingly viewed as among the favourites to replace Mrs May as Tory leader, Mr Hunt delivered a crowd-pleasing speech in which he included both his attack on Brussels and references to former Conservative prime ministers Winston Churchill and Margaret Thatcher.
Delivering the stern message to the EU, the UK's top diplomat said: "At the moment you seem to think the way to keep the club together is to punish a member who leaves.
"Not just with economic disruption. But even by breaking up the United Kingdom with a border down the Irish Sea.
"What happened to the confidence and ideals of the European dream? The EU was set up to protect freedom. It was the Soviet Union that stopped people leaving.
"The lesson from history is clear: if you turn the EU club into a prison, the desire to get out won't diminish it will grow – and we won't be the only prisoner that will want to escape.
"If you reject the hand of friendship offered by our prime minister, you turn your back on the partnership that has given Europe more security, more freedom and more opportunities than ever in history."
Also delivering a fierce rejection of the EU's plan for Northern Ireland to effectively remain in the bloc's customs union to prevent a hard border in Ireland, Mr Hunt channelled Mrs Thatcher to add: "If the only way to deal with the UK leaving is to try to force its break up, as someone much more distinguished than me once said, the answer is 'no, no, no'."
The start of the Tories' annual gathering has prompted a fresh round of infighting over Brexit.
Former foreign secretary Boris Johnson's latest attack on the prime minister's "deranged" Chequers plan on Sunday generated a strong counter-punch from Theresa May loyalists.
But Mr Hunt offered a plea for peace within Tory ranks, telling delegates: "If we are to unite the country, we must deliver not just a true Brexit for the 52% – but also a generous Brexit for the 48%. They are patriots too.
"So however fierce the debate, however high the passions, never forget that disunity and division won't give us a better Brexit but the wrong Brexit, a Corbyn Brexit or perhaps no Brexit at all.
"So let's argue our corners this week in Birmingham. But let's not carry on the fight after the moment we needed to come together."
0:29Mr Hunt's comparison of the EU to the Soviet Union was branded "wild and crass" and "downright offensive" by former Liberal Democrat leader Tim Farron, who supports the Best for Britain campaign for a fresh Brexit referendum.
He said: "The third-rate Thatcher tribute act might go down well in the hall but outside people will look at him as a fifth-rate Boris impersonator."
Earlier on Sunday, businessman Digby Jones used his speech – watched in person by Mrs May – to describe Mr Johnson as "irrelevant and offensive".
The House of Lords crossbencher, who was a minister in Gordon Brown's Labour government, saw his attack on the former foreign secretary widely applauded by Tory party members in the hall.
More from Brexit
1:01When asked in a Sky Data poll whether they'd be more likely to vote for a Conservative Party led by Theresa May or Boris Johnson, 40% of all respondents opted for Mrs May, compared to 24% who backed Mr Johnson.
When Conservative voters were asked the same question, 49% said they would prefer a party led by Mrs May, compared to 33% who said they would support Mr Johnson.
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