Campaigners for the UK to leave the European Union have put forward no "credible alternative" to membership, Philip Hammond said as he warned that Brexit could cost jobs and push up prices.
The Government has produced analysis by officials concluding that any of the alternative arrangements for relations with Europe would leave Britain worse off.
Prime Minister David Cameron said the analysis shows that the alternatives to EU membership would "damage Britain" - but the document was dismissed as a "dodgy dossier" by pro-Brexit Cabinet minister Iain Duncan Smith.
Foreign Secretary Mr Hammond said he was "not surprised" by his Cabinet colleague's comment and added: "The Government is mandated by Parliament to publish a series of documents and I probably could have guessed in advance what my colleague would describe them as."
The paper - which looks at arrangements adopted by countries including Norway, Switzerland and Canada as well as the option of falling back on World Trade Organisation (WTO) rules - warns that none is as good as the deal on offer with Brussels.
Mr Hammond warned that the alternatives would mean "working people would pay the price with few jobs and rising prices".
Speaking at the Chatham House foreign affairs think tank in London, Mr Hammond said: "The fact is, none of the bilateral free trade models would offer anything like the access that we now have to the single market and many of them would require adoption of EU regulations and freedom of movement rules."
He added that as well as the terms of trade with Europe, the UK would also face renegotiating deals on a global scale if it voted to leave on June 23.
"We currently benefit from EU trade deals with over 50 different countries. These deals have been based on the negotiating muscle of a bloc with 500 million consumers and a quarter of the world's GDP.
"Renegotiating them as a single country would take many, many years - years in which British businesses would be squeezed out of traditional markets, and with no guarantee at the end of the process that we could get terms as good as we have now.
"Some have said we should focus our attention on deals with the Anglosphere and the Commonwealth, but the EU already has or is negotiating trade deals with all the biggest Commonwealth countries and none of our allies wants us to leave the EU - not Australia, not New Zealand, not Canada, not the United States.
"In fact the only country that would like us to leave the EU is Russia and that should probably tell us all we need to know."
Mr Hammond conceded it was possible that the UK would be able to negotiate a better deal with the EU than other countries had managed but warned that the other 27 countries would "aggressively" protect their own interests and the process could take many years - or in Switzlerland's case two decades and more than 100 separate agreements.
It would mean "years of uncertainty for Britain just as we are getting back on our feet".
Work and Pensions Secretary Mr Duncan Smith said the "real uncertainty" lay with the EU "project".
"As each day passes we see yet another example - from the utter failure to cope with the migrant crisis, to the increasing disaster of the euro," he said.
"This dodgy dossier won't fool anyone, and is proof that Remain are in denial about the risks of remaining in a crisis-ridden EU.
"The truth is we won't copy any other country's deal. We will have a settlement on our own terms - and one that will return control of our borders, and money to Britain. That's the safer choice."