The comments from Ayatollah Ali Khamenei were part of a seven-page statement read word-for-word on Iranian state television and heavily promoted in the run-up to its release.
They also come two days after Iran marked the 40th anniversary of its 1979 Islamic Revolution amid heightened tensions between Tehran and Washington.
"About the United States, the resolution of any issues is not imaginable and negotiations with it will bring nothing but material and spiritual harm," Khamenei said.
The supreme leader went on to describe any negotiations as an "unforgiveable mistake."
He also said negotiations would be like "going on your knees before the enemy and kissing the claws of the wolf."
That tone is a long way from 2015, when Khamenei approved of talks between Iran and the United States that resulted in the nuclear deal between Tehran and world powers. The deal saw Iran limit its enrichment of uranium in exchange for the lifting of economic sanctions.
The statement by Khamenei, who has final say on all state matters, suggests more restriction by the current administration on engagement with the West.
Iranian President Hassan Rouhani, during a Cabinet meeting Wednesday, echoed Khamenei's remarks, saying: "If the Iranian nation surrenders to the United States, it should surrender until the end."
He said, however, that "Iran is about negotiation, but we are not ready to accept imposition, bullying, pressure and the trampling of our national rights."
President Donald Trump, who campaigned on a promise of tearing up the nuclear accord, withdrew the U.S. from the deal last May. Since then, the United Nations says Iran has kept up its side of the bargain, though officials in Tehran have increasingly threatened to resume higher enrichment.
Amid the new tensions, Iran's already-weakened economy has been further challenged. There have been sporadic protests in the country as well, incidents applauded by Trump amid Washington's maximalist approach to Tehran.
However, some have suggested Iranian leaders meet with Trump in a summit, much like North Korean leader Kim Jong-un.
Amir Mousavi, a former Iranian diplomat, has claimed that Trump sent a message to President Hassan Rouhani last week requesting direct talks.
Mousavi, speaking with Lebanese television station al-Mayadeen, said Trump is ready to visit Tehran and had sent several messages through intermediaries in Oman.
There has been no acknowledgment of such a request from Washington.
The Warsaw summit, which started Wednesday, was initially pegged to focus entirely on Iran. However, the US subsequently made it about the broader Middle East, to boost participation.
(This story has not been edited by Business Standard staff and is auto-generated from a syndicated feed.)