The document, updated every four years, sets priorities for America's military, law enforcement and foreign policy agencies. It drops some of the most controversial language from the Bush administration, like the phrase "global war on terror" and references to "Islamic extremism".
"The United States is waging a global campaign against al-Qaeda and its terrorist affiliates," the 52-page strategy document says.
"Yet this is not a global war against a tactic - terrorism, or a religion - Islam. We are at war with a specific network, al-Qaeda, and its terrorist affiliates."
The strategy also calls for US engagement with "hostile nations," closer relations with China and India, and a focus on strengthening the US economy.
Several of Obama's top advisers will discuss the new strategy in a carefully-orchestrated rollout in Washington on Thursday.
Hillary Clinton, the US secretary of state, is scheduled to give a speech at the Brookings Institution; and General James Jones, Obama's national security adviser, will discuss the document at Washington's Foreign Press Club.
Analysts in Washington have described the document as a clear break from former president George Bush's two national security strategies, issued in 2002 and 2006, which endorsed unilateral military action and spoke of the threat posed by "Islamic extremism".
Obama's strategy calls for the US to work within international institutions, like the United Nations and Nato, though it calls for significant reforms to those world bodies.
"An international architecture that was largely forged in the wake of World War II is buckling under the weight of new threats," the document says.
In a speech previewing the strategy on Wednesday, John Brennan, Obama's counterterrorism adviser, said the strategy reflected a shift in al-Qaeda's tactics. He pointed to several recent failed attacks against the US - the Times Square bombing attempt, and the failed Christmas Day airplane bombing - as examples of al-Qaeda's "less sophisticated" tactics.
"As our enemy adapts and evolves their tactics, so must we constantly adapt and evolve ours, not in a mad rush driven by fear, but in a thoughtful and reasoned way," Brennan said.