The Liberal Democrat Deputy Prime Minister made clear the depth of division between the coalition parties over Europe, saying that Mr Cameron had announced a five-year timetable for the "so-called" renegotiation and an in/out referendum on UK membership "for his own political purposes".
But he indicated that the referendum promise would not necessarily prevent Liberal Democrats entering into a renewed coalition with Conservatives in the case of a hung Parliament after the 2015 general election.
The Prime Minister was boosted today by a letter signed by 56 leaders of industry and the City, who welcomed his renegotiation proposals as "good for business and good for jobs in Britain".
They challenged Mr Clegg's argument that a protracted renegotiation will be bad for business, saying: "We need a new relationship with the EU, backed by democratic mandate."
And supporters of the plan welcomed German chancellor Angela Merkel's comment that she was "prepared to talk about British wishes... (and) find a fair compromise" as a sign that other European powers will be ready to engage with Mr Cameron's proposals for reform of the EU.
But Mr Clegg told LBC 97.3 radio: "I simply don't understand the point of spending years and years and years tying yourself up in knots, so-called renegotiating the terms of British membership in ways which at the moment at least are completely vague.
"I think that discourages investment and inhibits growth and jobs, which have to remain our absolute priority at a time when the economy is still struggling to recover...
"The things people worry about are immigration, jobs, crime on their streets. My worry is how are we going to address those concerns, which are the things people care about most, if you are going to spend the next five years touring European capitals coming up with ever more complex ways of renegotiating the status of Britain in the European Union?
"That seems to me to be not actually addressing the things that people care about most in their everyday lives."
Asked if his differences with Mr Cameron over Europe would block a future Tory-Lib Dem coalition, Mr Clegg replied: "I will follow the instructions of the British people.
"If a coalition is necessary following the votes of the British people, then we will play our part. I will always play a responsible role... to ensure this country has good government in the national interest."
Mr Cameron was meeting some of the European leaders face-to-face today for the first time since setting out his EU policy, as he attends in the World Economic Forum in Davos, Switzerland.
His speech to the gathering of political, economic and business leaders focused on Britain's priorities for its 12-month presidency of the G8, including counter-terrorism, tax and transparency.
But he touched on the European question, insisting that his EU policy was "not about turning our backs on Europe - quite the opposite".
He said: "This is about how we make the case for a more competitive, more open and more flexible Europe and how we secure the UK's place in it."
Setting out his case for reform of the EU, Mr Cameron added: "It is not just right for the United Kingdom, it is necessary for Europe.
"Europe is being out-competed, out-invested, out-innovated and it is time we made the EU an engine for growth, not a cause of cost for businesses and complaint for its citizens."
In his long-awaited speech in London yesterday, Mr Cameron said he hoped to persuade all 27 EU states to join in a new treaty to reform the EU for all its members, but was ready to demand a renegotiated status for Britain alone if other nations did not agree.
Draft legislation will be drawn up by the Conservative Party ahead of the election, and will be enacted by the end of 2015 if Tories win to pave the way for renegotiation and referendum within the next two years, he said.
"It is time for the British people to have their say," Mr Cameron said.
"It is time to settle this European question in British politics."
Mr Cameron said a new EU treaty should be driven by the five key principles of competitiveness, flexibility, return of powers to national governments, democratic accountability and fairness.
Crucially, he said it was time for the EU to ditch the universal commitment to "ever closer union" and accept that members can decide for themselves how deeply they want to integrate.
On his weekly call-in programme on LBC, Mr Clegg fielded a question about Mr Cameron's motives in committing himself to an in/out referendum by the end of 2017.
The Lib Dem leader responded: "I happen to disagree with the timing. The Prime Minister has chosen the timing for his own political purposes. I suspect it's got quite a lot to do with the fact that his party has had, for a long period of time, intense internal discussions about how they should play the European issue.
"My question is, why now, before we even know if there is going to be a new treaty, what the further integration in the euro zone is going to look like and whether that is going to ask anything of Britain?
"Why tie ourselves up in knots for years and years and years?"
He continued: "Of course today there is lots of focus on the referendum issue and lots of plaudits for the Prime Minister from the right- wing press, I totally understand that's predictable enough.
"I just think when people think ahead (about) what is going to happen now, what does renegotiation mean, exactly which powers come back, is the Conservative Party really going to be happy with the blueprint for what powers will be renegotiated? I think it will seem a lot more complicated and time-consuming in the future than it does today."
Mr Clegg said there was "a basic case for safety in numbers in a big, globalised world" that made EU membership good for Britain.
He added: "As the Americans have made very, very clear - and, to be fair, as David Cameron acknowledged in his speech - if we want to be taken seriously in Beijing, in Tokyo, in Washington, we have got to stand tall in our own back yard."
Finnish foreign minister Alexander Stubb praised Mr Cameron's speech as "constructive".
"We need Britain in Europe and Europe needs Britain as well," he told BBC Radio 4's Today programme. "It's going to be a long path but it's very good for the British EU debate."
Mr Stubb expressed optimism about Mr Cameron's chances of achieving a renegotiation.
"There has been a lot of differentiation inside the EU over its history," he said. "A lot of countries are not in the euro, lots are not in (the) Schengen (Agreement), there are some outside defence and hundreds of directives not implemented.
"Of course we have stick to the bulk of it but of course we can take a few raisins out of the bun."