In an address marking the end of the Muslim holy month of Ramadan, Khamenei said he wanted politicians to examine the agreement to ensure national interests were preserved, as Iran would not allow the disruption of its revolutionary principles or defensive abilities.
"Whether the (nuclear) deal is approved or disapproved, we will never stop supporting our friends in the region and the people of Palestine, Yemen, Syria, Iraq, Bahrain and Lebanon. Even after this deal our policy towards the arrogant US will not change," he said.
Under the deal agreed on Tuesday, sanctions will be gradually removed in return for Iran accepting long-term curbs on a nuclear program that the West has suspected was aimed at creating a nuclear bomb. Iran denies it seeks a nuclear bomb.
"The Americans say they stopped Iran from acquiring a nuclear weapon," Khamenei said at Tehran's Mosala mosque. "They know it's not true. We had a fatwa (religious ruling), declaring nuclear weapons to be religiously forbidden under Islamic law. It had nothing to do with the nuclear talks."
He said slogans of "Death to America" and "Death to Israel" chanted at demonstrations in Iran this week supporting the Palestinian cause showed what Iranians think and "shook the atmosphere of the country".
"We have repeatedly said we don't negotiate with the US on regional or international affairs; not even on bilateral issues. There are some exceptions like the nuclear program that we negotiated with Americans to serve our interests ... US policies in the region are diametrically opposed with Iran's policies."