His comments come after President Donald Trump's administration ramped up pressure on North Korea on Sunday, warning Pyongyang will be "destroyed" if it refuses to end its "reckless" nuclear and ballistic missile drive.
"There are many military options, in concert with our allies, that we will take to defend our allies and our own interests," Mattis told Pentagon reporters.
He did not provide details, but he responded affirmatively when asked if these included options that would not put Seoul at grave risk.
Mattis also confirmed that the US and Seoul had discussed the option of sending limited-size "tactical" nuclear weapons to South Korea.
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North Korea's weapons drive is set to dominate Trump's address to the United Nations General Assembly on Tuesday and his meetings with South Korean and Japanese leaders this week.
Tensions flared when Kim Jong-Un's regime tested what it termed a hydrogen bomb many times more powerful than its previous device.
The North also fired a ballistic missile over Japan and into the Pacific on Friday, responding to fresh new UN sanctions with what appeared to be its longest-ever missile flight.
Amid calls for the United States and Japan to shoot down such missiles, Mattis said there was no need to do so because they were not a direct threat.
"The bottom line is that in the missiles, were they to be a threat, whether it be the US territory Guam, obviously Japan, Japan's territory, that would elicit a different response from us," he said.
