The European Commission President claimed the bloc had to push for more defence and security cooperation on its own.
He told a conference in Prague: “Our deference to NATO can no longer be used as a convenient alibi to argue against greater European efforts.
“We have no other choice than to defend our own interests in the Middle East, in climate change, in our trade agreements.”
He went on to say that the EU’s plans to deepen security and defence ties were not aimed at weakening NATO.
Mr Juncker said: “No-NATO is not an option for the EU. It would be a disaster for the EU.”
He said it was time to integrate militaries and defence industries, seizing on the strong backing from France’s new president and Britain’s decision to leave the bloc.
Claiming he can “see the tide turning”, Mr Juncker cited growing support in EU capitals for military cooperation, notably from French President Emmanuel Macron.
He said: “The call I make today is not only in favour of a Europe of defence – it is a call in defence of Europe.”
Although the EU has more than a dozen military missions abroad, the world’s biggest trading bloc has never been able to match its economic might with broad defensive power, preferring to rely on the North Atlantic Treaty Organisation.
Britain had long blocked EU defence integration, fearing a European army that would challenge national sovereignty.
NATO broadly supports EU defence integration, as 22 EU states are members of the US-led alliance.
Chiding the bloc for decades of failed attempts to work together on defence since the 1950s, Mr Juncker said that even before the election of President Donald Trump, the United States considered it was paying too much for wealthy Europe’s security.
With Trump, who has sharply criticised European states for not spending enough on defence and has refused to explicitly support NATO, the reality was more stark, he said.
The EU has long been able to boast of a “soft power” with recent diplomatic successes including its role in brokering the 2015 Iran nuclear deal.
But the EU’s inability to help bring peace to Syria or significantly influence events abroad, from Turkey to the Middle East, meant that soft power was not enough, Mr Juncker said.