"Let me be absolutely clear: leaving the EU would be economic suicide," he will say in a London speech.
He will point out that three million British jobs are linked to the single market, calling it "the world's biggest borderless market place... Where Britain conducts half of its business," according to extracts of the speech released to the press.
"We simply will not be taken seriously by the Americans, the Chinese, the Indians, all the big superpowers if we're isolated and irrelevant in our own backyard," he will add.
The leader of the Liberal Democrats, the minor partner in Britain's coalition government, will single out the eurosceptic UK Independence Party (UKIP) and the right wing of the Conservative Party, the coalition's main partner, as forces of isolationism.
"We need to start challenging some of the ludicrous mythmaking by the isolationists now," he will urge.
"Brussels isn't perfect by any means. But it's just not true that it's some kind of sinister super-bureaucracy -- the Commission is smaller than Birmingham City Council" in central England.
Cameron has also promised to renegotiate Britain's terms of membership ahead of the referendum.
It is because of this that Clegg said he had written to 100 "leading organisations covering areas such as policing, trade, finance, human rights, the environment and child protection" to urge them to publicly declare why Britain is better off "in".
