"The world is as dangerous as it has been for generations and Europe is in the middle of it," the European Commission president told a Brussels conference.
Von der Leyen pointed to a "new league of authoritarians" including Russia, Iran and North Korea that was looking to "stretch our democracies to breaking point".
"This is why it is time for the European awakening on defence and security," she said.
Russia's 2022 invasion of Ukraine was billed at the time as a wake-up call for Europe after decades of under-investment in its defences after the Cold War.
The EU has since launched initiatives to ramping up military production.
But more than two years into the war, while Russia has put its economy on a war-footing, the EU is still struggling to meet Ukraine's needs and build up its own forces.
With Ukraine's forces increasingly struggling along the front line, there are growing fears that a wider conflict could engulf Europe should Moscow triumph.
"The threat of war may not be imminent but it is not impossible. We should be prepared," von der Leyen said.
"That starts with the urgent need to rebuild, replenish and transform member states' armed forces."
A sense of urgency in Europe has been heightened by the possible return to the White House of an isolationist Donald Trump after US elections in November.
"European sovereignty will never be at the expense of our partners and friends. And it will certainly never affect the importance and the need for our NATO alliance," von der Leyen said.
Brussels last month put forward a 1.5 billion euro ($1.6 billion) strategy to step up defence production, but officials say this is not sufficient.
"Is it enough -- no. Do we need more -- yes," said EU internal market commissioner Thierry Breton, who has spearheaded the defence push.
France, Estonia and other countries have pitched the need for a larger programme funded by joint borrowing that could rise to 100 billion euros.
But that push has got short shrift from so-called frugal countries led by Germany.
Brussels is to come up with new proposals on its defence push by a summit of the bloc's leaders in June.
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