Mattis, a retired four-star general who saw his Marines killed by Tehran-backed militias in Iraq, has frequently lambasted Iranian actions in the Middle East.

But he has been a staunch advocate of working with allies and became a quiet defender of the Iran deal as Trump mulled pulling out.

"We will continue to work alongside our allies and partners to ensure that Iran can never acquire a nuclear weapon, and will work with others to address the range of Iran's malign influence," Mattis told a Senate panel.

"This administration remains committed to putting the safety, interests and well-being of our citizens first."

Trump defied the wishes of major world powers by announcing Tuesday that the US would pull out of the historic nuclear accord and impose new sanctions on Tehran.

The agreement puts limits on Iran's nuclear program in exchange for lifting international sanctions.

In October, Mattis said it was in the US national interest to remain in the deal.

In January, he said the Iran deal was "imperfect" but added that "when America gives her word, we have to live up to it and work with our allies."

Last month, he said the deal allowed for "pretty robust" inspections of Iranian facilities.

Still, Mattis blasted Iran for its "malign activities," including its support for Syrian President Bashar al-Assad and for backing Huthi rebels in Yemen.

"We have not seen any drawdown or reduction in Iran's malicious activities and malign activity across the region," Mattis said.

"At the same time we have walked away from the JCPOA because we found it was inadequate for the long-term effort," he added, using the formal abbreviation for the accord.

Democratic Senator Dick Durbin said Trump's decision to pull out of the deal was "not only wrong but reckless," and questioned whether America would be able to convincingly work with allies in the future on Iran.

"Now that the United States is walking away from it, I cannot believe it will inspire any confidence among our allies about our word and our reliability in the future when it comes to these agreements," Durbin said.

Mattis risks being isolated by Trump's more hardline coterie of advisors, including national security advisor John Bolton, an Iraq War-era hawk who has advocated military action in both Iran and North Korea.