With almost all votes counted, Finance Minister Yanis Varoufakis said the Greek people had sent back the "ultimatum" from the eurozone and the International Monetary Fund (IMF).
The Greek finance minister, whose forceful denunciations of creditors alienated many of his euro zone colleagues, said Prime Minister Alexis Tsipras believed it would help smooth the path to a new aid deal.
His resignation comes after Greeks delivered a resounding 'No' to the conditions of a rescue package with international creditors, casting the country into uncharted waters and a possible exit from Europe's common currency.
With relations already frosty, Varoufakis infuriated Greece's European partners last week when he accused creditors of using "terrorism" against the Greek people to intimidate them into accepting more austerity.
In a statement, Varoufakis said he had been "made aware" that some members of the euro zone considered him unwelcome at meetings of finance ministers, "an idea the prime minister judged to be potentially helpful to him in reaching an agreement".
"For this reason I am leaving the ministry of finance today."
"I consider it my duty to help Alexis Tsipras exploit, as he sees fit, the capital that the Greek people granted us through yesterday's referendum," Varoufakis said.
"And I shall wear the creditors' loathing with pride."
The result - with more than 60pc voting No - represents a sensational victory for the country's radical left Prime Minister Alexis Tsipras, who had gambled all on the outcome of the referendum.
But it leaves the country facing an uncertain future - with opponents warning he needs a new bailout deal fast if he is to avoid a catastrophic financial crash that could send it spinning out of the single currency.
With Greek banks rapidly running out of cash, European Council President Donald Tusk has called an emergency summit of eurozone leaders for tomorrow after appeals by German Chancellor Angela Merkel and French President Francois Hollande
Ms Merkel and Mr Hollande - the leaders of the two biggest eurozone members - will meet today in Paris for crisis talks.
In London, David Cameron will meet Chancellor George Osborne, Bank of England Governor Mark Carney and other senior officials to discuss the likely impact on the UK.
In Athens, jubilant supporters of the Syriza government poured into Syntagma Square opposite the Greek parliament to celebrate what they regarded as a famous triumph and a decisive rejection of austerity.
Mr Kouvelakis said Syriza was now focusing on a return to negotiations, but would not accept the previous deal that was offered.
"The Greek people have made it absolutely clear they will not accept this deal," he said.
Mr Kouvelakis, who teaches at King's College London, said it would now be up to the ECB as to whether Greek banks would reopen tomorrow.
"This will depend on a decision by the ECB and it will show how serious Europe is about proper negotiation," he told the Irish Independent.
Meanwhile, European investors were braced for tumbling stock markets today after Greeks overwhelmingly rejected the bailout terms of their creditors.
The No vote is set to ensure that Greece's creaking banking system will continue to be starved of liquidity, keeping them closed beyond the end of their mandated bank holiday, which is due to end tomorrow.
Sources insist the banks will be unable to open in the forseeable future and that ATMs will begin running out of cash by the middle of this week.
At least one of the four major banks was reported to have all but run out of cash, despite the imposition of capital controls which have limited ATM transactions to €60 a day.
The Bank of Greece was due to request an additional injection of emergency liquidity assistance from the ECB.
However, with voters rejecting the conditions of the country's paymasters, the ECB is almost certain to keep liquidity assistance frozen at nearly €88.4bn.
Mr Varoufakis was due to discuss extending capital controls measures with the Greece's senior bankers last night. Greek stock markets have also been suspended.
European Parliament president Martin Schulz warned a No vote in the referendum would mean Greeks could no longer use the euro, forcing them to print IOUs to pay public sector salaries and pensions, and introduce another currency: