Washington's top diplomat joined foreign ministers of the 10-member Association of Southeast Asian Nations in Kuala Lumpur at a meeting on Thursday that includes Australia, China, the European Union, Japan, Russia, South Korea and Russia, and others.
The visit is part of an effort to renew US focus on the Indo-Pacific and look beyond conflicts in the Middle East and Europe that have consumed much of the Trump administration's attention.
"It is our view, our strong view, and the reality that this century and the next, the story of the next 50 years, will largely be written here in this region, in this part of the world," Rubio told the gathering of ASEAN ministers.
"When I hear ... that perhaps the United States or the world might be distracted by events in other parts of the planet, I would say distraction is impossible," said Rubio, who doubles as national security adviser.
However, Trump's global tariff strategy is likely to cast a shadow over the trip after he unveiled steep tariffs from August 1 on seven ASEAN members, including Malaysia, as well as on close allies Japan and South Korea.
Rubio would nevertheless seek to firm US ties with partners and allies unnerved by the tariffs, and was likely to press the case that the United States remained a better partner than China, Washington's main strategic rival, experts said.
China's Foreign Minister Wang Yi and Russian counterpart Sergei Lavrov are also attending the event.
Rubio was set for talks with Lavrov later on Thursday that will be their second in-person meeting, at a time when Trump has grown increasingly frustrated with Russian President Vladimir Putin as the war in Ukraine drags on.
On Monday, a senior State Department official said Rubio's priorities for the trip included reaffirming Washington's commitment to the region, not just for its sake but because it promoted American prosperity and security.
Security co-operation was a top priority in areas such as the strategic South China Sea and combating transnational crime, narcotics, scam centres, and people-trafficking, the official said.
As well as their tariff unease, many have doubts about the willingness of Trump's "America First" administration to fully engage diplomatically and economically with the region.
Trump will impose a tariff of 25 per cent on Japan and South Korea and has taken aim at ASEAN nations, with a levy of 25 per cent on Malaysia, 32 per cent on Indonesia, 36 per cent on Cambodia and Thailand, as well as 40 per cent on Laos and Myanmar.
He has also stepped up to 20 per cent from 17 per cent the tariff on US defence treaty ally the Philippines.
Only Vietnam has secured a deal with Trump to lower its levy to 20 per cent from an initial 46 per cent.
Trump has also upset another key Indo-Pacific ally, Australia, which said on Wednesday it was "urgently seeking more detail" on his threat of 200 per cent tariffs on pharmaceutical imports.
A draft joint communique seen by Reuters shows that ASEAN foreign ministers will express "concern over rising global trade tensions and growing uncertainties ... particularly the unilateral actions relating to tariffs".
Monday's draft uses language similar to an ASEAN leaders' statement in May, saying tariffs are "counterproductive and risk exacerbating global economic fragmentation".
