"When they are ready, we are ready," von der Leyen said on Friday.
With backing from Europe leaders, she said she the commission would "provisionally apply the agreement" after Uruguay and Argentina ratified the EU-Mercosur trade deal on Thursday.
The deal has been negotiated for a quarter-century among countries that are now home to more than 700 million people and account for a quarter of global gross domestic product, creating one of the world's largest free trade zones.
It follows global trade shocks from the tariffs imposed by the United States and throttling of critical mineral supplies for China that pushed the 27-nation EU to forge a raft of free trade deals with other nations across the world.
However, the deal has faced vehement opposition from Europe's agriculture sector and was expected to face tough questions by elected representatives in European Parliament.
Von der Leyen is basically sidestepping for now those MPs - an unusual move for the European executive and one likely to prompt criticism.
"Mercosur embodies the spirit in which Europe is acting on the global scene," von der Leyen said at a news conference.
No questions were allowed.
"Our businesses, our workers, and our citizens will reap the benefits, and they should reap them as soon as possible," she said.
"This is about resilience, this is about growth, and Europe shaping its own future."
She also acknowledged that the "agreement can only be fully concluded once the European Parliament has given its consent".
"So the commission will continue closely with all EU institutions, member states, and stakeholders to ensure a smooth and transparent process," she said.
