Over an extended dinner at an informal summit in the Belgian capital, the Prime Minister warned fellow leaders they could not "shrug off" Sunday's results, insisting they needed to be more ruthless about the EU's priorities.
The leaders' discussions focused on the process of finding a replacement for European Commission President Jose Manuel Barroso, whose term ends in October.
But Mr Cameron signalled he was deeply opposed to the current front-runner, the former Luxembourg Prime Minister Jean-Claude Juncker, a veteran federalist.
The PM stressed the importance of a candidate who was focused on openness and flexibility instead of being bound up in the Union's past.Although Mr Cameron cannot formally veto Mr Juncker, who has been nominated as the candidate of the European People's Party grouping - the block the British premier pulled the Tories out of over its federalist sympathies - it is unlikely the European Council, made up of the EU's 28 national heads of government, would force through Mr Barroso's successor without unanimous backing.
As he arrived for the talks, the Prime Minister said: "Europe cannot shrug off these results. We need an approach that recognises Europe should concentrate on what matters; on growth and jobs and not try and do so much.
"We need an approach that recognises Brussels has got too big, too bossy, too interfering. We need more for nation states. It should be nation states wherever possible and Europe only where necessary.
"Of course, we need people running these organisations that really understand that and can build a Europe that is about openness, competitiveness and flexibility; not about the past."
Earlier, his spokeswoman was asked if the PM felt the Euro poll results would help him secure his reforms on repatriating powers to Britain and on creating more free trade. She replied: "There is a kind of sense over the last few days that this is a real moment for change and a fresh approach."
Ukip leader Nigel Farage insisted there was "nobody more fanatical about building the United States of Europe" than Mr Juncker and argued his candidacy had come "just at the moment European electors have made it clear they are going in the wrong direction".
The 28 leaders also focused on the "political earthquake" which saw not only Ukip top the polls in Britain but also the far-right Front National come first in France and the extreme-left Syriza movement take top spot in Greece. The Eurosceptic Five Star movement came second in Italy and the anti-euro Alternative for Germany won seven seats although broadly pro-European parties still dominate the European Parliament.
In Paris, Francois Hollande, France's Socialist President, addressed the rise of Eurosceptic and far right parties, admitting the EU had become too remote and complex and needed to reform, concentrating on boosting jobs. "This vote is there," he insisted, "and it needs to be confronted."
Before travelling to Brussels, Mr Cameron made a series of phone-calls to his European counterparts, including Mr Hollande, German Chancellor Angela Merkel, the Polish premier Donald Tusk and Swedish PM Fredrik Reinfeldt, to try to rally support for reform.
Last night, Labour's Douglas Alexander stressed Europe now faced a "significant reform moment that must be seized".
But he noted how Mr Cameron still seemed either unwilling or unable to set out what changes he wanted to see at an EU level.
He said: "Only days after the European elections, it is clear that Europe has to work better for Britain, but instead of building alliances with our European partners for reform, his party is proposing pacts with Ukip candidates and deals with fringe political parties in the European Parliament."
Earlier, the PM faced calls from business leaders, including some of the Tories' biggest donors, to resist the rise of Ukip by laying out in detail his plans for renegotiation of Britain's membership of the EU. They warned "vague promises" would only increase support for the anti-Brussels party.