If EU leaders back Jean-Claude Juncker for the post of European Commission president this week it would be "flicking two fingers" at voters across the continent who had expressed concerns about Brussels, Iain Duncan Smith said.
The former Tory leader said the rise of Eurosceptic parties had sent a "seismic message" and accused heads of government of being "utterly complacent" about the situation.
David Cameron will risk deepening divisions between the UK and EU by forcing leaders from across the 28-member bloc to vote on the issue at the European Council summit this week unless his counterparts are prepared to consider an alternative candidate.
The move would mark a distinct break from the way that the commission president is usually chosen, with the nomination agreed by consensus between the leaders.
The Prime Minister's decision to oppose Mr Juncker's nomination looks set for failure, after nine centre-left leaders, including French president Francois Hollande and Italy's Matteo Renzi declared their support for Mr Juncker - the candidate nominated for the presidency by the centre-right European People's Party (EPP).
The EPP is the largest party in the European Parliament following the elections last month, but Mr Cameron has made clear he will "fight this right to the very end" rather than allow the European Council, made up of leaders of EU governments to rubber stamp Mr Juncker's appointment.
Mr Duncan Smith, a prominent Eurosceptic within the Cabinet, said: "I was talking to the Prime Minister the other day and he said there are a load of countries there who share his view on this, they think this is the wrong man, the Italians were saying it, many were saying it, even privately I understand many Germans say it."
The Work and Pensions Secretary said Mr Juncker was "by no means a reformer" and backed the Prime Minister's stance, saying the EU needed to be "roughed up a bit about this".
He told BBC Radio 5 Live's Pienaar's Politics: "If they give Jean-Claude Juncker a job this is like literally flicking two fingers at the rest of Europe and saying to all the people out there 'we know that you voted the way you did but you are wrong and we are just going to show you how wrong you are by carrying on as though nothing happened'."
Mr Duncan Smith indicated he would be prepared to vote against EU membership in the referendum promised by Mr Cameron in 2017, even if the Prime Minister recommended staying in after a renegotiation.
He said: "I have always been of the view that there needs to be major change within the European Union if Britain is to honestly think this is a viable enterprise for us. It's not right now, it's heading in the wrong direction."
On his own position he said "at the end of the day every elected MP has a free vote, they have to take the decision of their conscience" and added: "When it's something as big as this you have to vote for what you think is best for your country.
"But I will help, support and assist the Prime Minister in getting the best deal and then I will make a view on that when it comes back."
If Mr Juncker got the job of European Commission president there would still be the possibility of reform if EU leaders were committed to it, but if they did not follow that course it would be "very bleak" for Britain's chances of remaining within the EU.
"At the end of the day Jean-Claude Juncker wields a certain amount of power, but nothing like as much still as the governments of Europe. So the key question really is are these governments of Europe prepared, regardless now who becomes president, to actually say this place needs dramatic change and reform - decentralisation, much more power going back to nation states again," Mr Duncan Smith said.
"Are they going to do that? If they don't do that then it does make the prospect for Britain being in Europe very bleak indeed."
Mr Cameron will spell out his concerns to European Council president Herman Van Rompuy in No 10 tomorrow, ahead of a two-day meeting of leaders on Thursday and Friday.
Tory former defence secretary Liam Fox said that if Mr Cameron did not "fight a battle and take a bloody nose" over Mr Juncker's candidacy it would put the EU "on the juggernaut route" to ever closer union.
He told BBC One's Andrew Marr Show: "The Juncker agenda is wrong for the people of Europe, including the people of Britain, and the British Prime Minister is right to stand up against it."
An opinion poll showed that almost half of Britons would vote to leave the EU under the current membership terms.
The Observer/Opinium poll found that 48% of people would "definitely" or "probably" vote to leave the EU, while 37% said they would definitely or probably vote to stay in.
The poll found that if Mr Cameron was able to secure a deal which "redefined the terms of Britain's membership" then 42% would definitely or probably vote to remain in the EU, with 36% saying they would probably or definitely vote to sever ties with Brussels.
But just 18% of those polled believed it was quite likely or very likely that Mr Cameron would be able to secure "satisfactory" terms, with 55% saying it was quite or very unlikely.
:: Opinium carried out 1,946 online interviews from June 17 to 19. Data were weighted to ensure a nationally representative sample.
Shadow foreign secretary Douglas Alexander said: " The responsibilities on David Cameron this week are clear; he needs to deliver a president of the commission who will make Europe work better, and make Europe work better for Britain.
"There can be no excuses. David Cameron has a clear mandate from political parties here in the UK - including Labour - to build consensus across Europe for an alternative candidate for president of the commission.
"Getting the right candidate is ultimately a test of David Cameron's influence with our allies to secure the best deal for Britain in Europe.
"Even his strongest supporters recognise that so far the Prime Minister has badly misjudged these vital negotiations, and his public anger appears a very poor substitute for private influence.
"It was not just a bad negotiating approach, but it was bad for Britain for David Cameron to appear to threaten exit from Europe at a key moment of these discussions.
"In the past we've seen David Cameron flounce out of the European negotiating room to little effect.
"And even David Cameron's own backbenchers know, bluster and belligerence are an unconvincing substitute for influence and leadership.
"So in the vital closing hours of negotiations, it's time for leadership, not excuses from David Cameron."