He spoke in South Korea, where he had been reaffirming US support, before flying to Tokyo.
James Mattis also reconfirmed plans to deploy a US missile defense system in South Korea later this year.
North Korea’s repeated missile and nuclear tests and aggressive statements continue to alarm and anger the region.
The US has a considerable military presence in South Korea and Japan, as part of a post-war defense deal. There are just under 28,500 US troops in the country, for which Seoul pays about $900 million annually.
President Donald Trump has previously said he wants both South Korea and Japan to pay more towards maintaining that presence.
According to the Pentagon, James Mattis used his visit to reassure South Korea that the Trump administration “remains steadfast” in its “iron-clad” defense commitments to the region.
Speaking after talks at the defense ministry with his South Korean counterpart Han Min-koo, James Mattis told reporters that “any attack on the United States, or our allies, will be defeated, and any use of nuclear weapons would be met with a response that would be effective and overwhelming”.
North Korea conducted its fifth test of a nuclear device in 2016, and claims it is capable of carrying out a nuclear attack on the US, though experts are still unconvinced its technology has progressed that far.
After visiting South Korea, James Mattis flew to Japan, where there are a further 50,000 US soldiers plus their dependants and support staff in Japan. The US paid about $5.5 billion for its Japanese bases in 2016, with Japan paying a further $4 billion.
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