In a speech to mark the 35th anniversary of the 1979 Islamic revolution, Ayatollah Ali Khamenei, the most powerful figure in Iran, added that officials seeking to revive the economy should not rely on an eventual lifting of sanctions but rather on home-grown innovation.
"American officials publicly say they do not seek regime change in Iran. That's a lie. They wouldn't hesitate a moment if they could do it," he was quoted as saying by the semi-official Fars news agency.
Khamenei made no mention of talks between Iran and world powers intended to settle a decade-old dispute about the Islamic Republic's nuclear programme.
But he reiterated that in dealing with "enemies", Iran should be prepared to change tactics but not compromise on its main principles.
Khamenei added: "The solution to our economic problems is not looking out and having the sanctions lifted ... My advice to our officials, as ever, is to rely on infinite indigenous potentials."
He added: "Our (hostile) stance toward the United States is due to its controlling and meddlesome attitude."
Khamenei's comments about hostility reflect his long standing animosity towards the United States, seen as the arch-enemy by Iranian authorities.
The United States and Iran have had no official ties since 1980 after Iranian students occupied the U.S. embassy in Tehran, taking 52 diplomats hostage in protest against Washington's admission of the former Shah after he was toppled by the Islamic revolution.
But Khamenei has given his guarded support to the nuclear negotiations being led by the new reformist government of President Hassan Rouhani and Foreign Minister Mohammad Javad Zarif.