Ayatollah Ali Khamenei's comments follow reports about a possible meeting between President Donald Trump and his Iranian counterpart, Hassan Rouhani.
“Americans have to realize that warmongering and warmongers are not to their benefit,” the Iranian president said in televised remarks.
Iran announced it has begun using advanced centrifuges to enrich uranium.
Donald Trump had said Monday at the G-7 that there's a "really good chance" that he and Hassan Rouhani could meet to discuss their nuclear impasse.
European leaders have struggled to calm the deepening confrontation between Iran and the United States since Trump pulled out of the 2015 nuclear deal.
The new threat comes days after President Hassan Rouhani said the nation could push its uranium enrichment level to "any any amount we want."
A diplomatic conflict between Tehran and Washington has flared since the U.S. pulled out of the 2015 Iranian nuclear deal.
President Hassan Rouhani threatened to do more if world powers didn't protect Iran from the impact of U.S. sanctions.
One year after threatening North Korea before the General Assembly, the U.S. president targets Iran.
President Hassan Rouhani claimed an unnamed U.S.-allied country was behind Saturday's attack.
Trump announced Monday that he would meet "anytime" with Iranian President Hassan Rouhani with "no preconditions."
But it's music to the ears of foreign policy hawks like John Bolton and Lindsey Graham.
"People are wondering why the president would threaten them with nuclear war, when he let Vladimir Putin practically run his fingers through his hair?"
"NEVER GONNA MAKE YOU CRY."
On Monday, the Iranian foreign minister warned Trump to "be cautious" -- echoing an earlier tweet penned by the U.S. president threatening Iran.
The comment comes after Iran's Hassan Rouhani said any conflict with his country would be "the mother of all wars."
The U.S. withdrawal from the accord was a “violation of morals,” Iranian President Hassan Rouhani said.
“The deal is not dead. There’s an American withdrawal from the deal but the deal is still there."
Those who said the United States could never be trusted have been proved right.
France, the U.K. and Germany had attempted a last-ditch push to get Trump to change his mind in recent weeks.