Thousands took to the street, calling on Supreme Leader Ali Khamenei to resign.
Iran's Foreign Minister Javad Zarif had previously said that Iran did not plan to escalate tensions further.
Ali Akbar Velayati said that the U.S. "took a foolish move" by assassinating Qassem Soleimani "and they must leave the region."
Demonstrators caused havoc at the U.S. Embassy in Iraq after retaliatory American airstrikes killed 25 members of an Iran-backed militia.
President Hassan Rouhani added that the "outrageous and idiotic" U.S decision to impose sanctions meant the "certain failure" of American efforts.
"No one can defeat a nation which pursues resistance," Iranian President Hassan Rouhani said in a televised address, claiming the U.S. and its allies were to blame for the country's poor economy.
Ayatollah Ahmad Khatami pointed out that nuclear bombs are "clearly" against Islamic (or Sharia) law.
"The Americans happily say that these sanctions are unprecedented in history. Yes, they're unprecedented. And the defeat that the Americans will face will be unprecedented, God willing," Supreme Leader Ayatollah Ali Khamenei said.
"Even if Trump himself is interested in negotiations, the people around him are committed to not letting that happen," said the president of the National Iranian American Council.
Secretary of State Mike Pompeo said on Sunday that President Donald Trump is "happy to talk with folks at any time."
Iranian military spokesman Abolfazl Shekarchi has said the attack was carried out by groups linked to the U.S. and Israeli intelligence.
"Currently, Iran and its nuclear program have turned into [one of] the most significant concerns of the EU," Federica Mogherini, the EU representative for foreign affairs and security policy, said Friday.
"Those who threaten to wipe us out, put themselves in a similar danger, and in any event will not achieve their goal," Netanyahu said from a nuclear facility on Wednesday.
Iranian President Hassan Rouhani and Foreign Minister Javad Zarif initially argued that the deal would bring a windfall of foreign investment, but that promise did not materialize.
Despite Khamenei promising that war is not an option, he also said that dialogue with Washington is not on the table.
Iran's Ayatollah Ali Khamenei said Mecca "belongs to all Muslims," and their security during Hajj was a God-given right that Saudi Arabia fails to uphold.
"The one who must leave is the U.S., not the Islamic Republic. We are from this region: the Persian Gulf is our home; West Asia is our home," Khamenei said.
The Ayatollah said Muslims must resist arrogant western nations.
Iranian officials have called for users to leave the encrypted messenger and move to a homemade alternative, complete with "death to America" and "Let's pray" stickers.
Iran is sending officials to Lebanon, Iraq and Syria as tensions mount with Israel, Saudi Arabia and the U.S.
Iranian supreme leader Ayatollah Ali Khamenei says it's the Islamic Republic's duty to protect citizens from social media companies stealing their data.
The U.S. and Iran are both fighting ISIS, but accuse one another of destabilizing the Middle East.
Iran's supreme leader Ayatollah Ali Khamenei said, "what the Saudis do...is certainly a betrayal of the Islamic Ummah and the Muslim World."
At least 21 people have been killed in the protests, the largest in Iran since 2009.
In 1953, the CIA backed a coup against democratically elected Iranian Prime Minister Mohammad Mossadegh, restoring absolute power to the Shah.
Iranian officials accused the U.S. of once again meddling in their internal affairs and offered to help Trump address his own hunger problem.