"The enemies have united and are using all their means, money, weapons, policies and security services to create problems for the Islamic regime," Ayatollah Ali Khamenei said in a speech carried on state television.
Iranian officials have said online accounts in the United States, Britain and Saudi Arabia are fomenting protests.
A fifth night of unrest saw six protesters killed during an attack on a police station in Qahderijan in the central province of Isfahan, state TV said Tuesday.
At least three other towns near the cultural hub of Isfahan also saw violence overnight, causing the deaths of a young member of the Revolutionary Guards, a policeman and a bystander.
The estimated death toll is now 21 since protests began in second city Mashhad and quickly spread to become the biggest challenge to the Islamic regime since mass demonstrations in 2009.
"The enemy is always looking for an opportunity and any crevice to infiltrate and strike the Iranian nation," Khamenei said.
The unrest appears leaderless and focused on provincial towns and cities, with only small and sporadic protests in Tehran on Monday evening where a heavy police presence was reported.
As violence has spread, authorities have stepped up arrests, with at least 450 people detained in the capital since Saturday and 100 more around Isfahan on Monday, officials told local media.
A Revolutionary Guards spokesman said they had not been requested to intervene directly, but they requested the public to report "seditionist elements".
"We will not permit insecurity to continue in any way in Tehran. If it continues, officials will take decisions to finish it," said Esmail Kowsari, a deputy commander for a local branch of the Guards, on state television.
Ali Shamkhani, secretary of the Supreme National Security Council, described the unrest as a "proxy war against the Iranian people".
"Hashtags and messages about the situation in Iran come from the United States, Britain and Saudi Arabia," he told local media.
President Hassan Rouhani has tried to play down the unrest, which began over economic grievances Thursday but quickly turned against the regime as a whole with chants of "Death to the dictator".
"This is nothing," he said in a statement on the presidency website on Monday, vowing the nation would deal with "this minority who... insult the sanctities and values of the revolution".
"With every day that passes, the crimes of those arrested become more serious and their punishment will become heavier. We no longer consider them as protesters demanding rights, but as people targeting the regime," the head of Tehran's revolutionary court, Moussa Ghazanfarabadi, told the conservative Tasnim news agency.
Rouhani came to power in 2013 promising to mend the economy and ease social tensions, but high living costs and a 12 percent unemployment rate have left many feeling that progress is too slow.
The young are most affected, with as many as 40 percent out of work according to analysts, and rural areas particularly hard-hit.
'People have had enough'
"People have had enough, especially the young people. They have nothing to be happy about," Sarita Mohammadi, a 35-year-old teacher in Tehran, told AFP.
"The situation is far worse in provinces. Agriculture has been destroyed. I know many who have left the north of the country to come to Tehran to work," she added.
Rouhani acknowledged there was "no problem bigger than unemployment" in a speech on Sunday, and also vowed a more balanced media and more transparency.
US President Donald Trump, who has repeatedly criticised Tehran over four days of demonstrations, said it was "time for a change" and that Iran's people were "hungry" for freedom.
The European Union on Monday pushed Iran to guarantee the right to protest and separately British Foreign Secretary Boris Johnson said "the UK is watching events in Iran closely".
"We believe that there should be meaningful debate about the legitimate and important issues the protesters are raising and we look to the Iranian authorities to permit this," Johnson said in a statement.
Turkey on Tuesday expressed concerned about the protests in a statement that called for "common sense" to "prevail to prevent any escalation".
In 2009, authorities ruthlessly put down protests against the re-election of hardliner Mahmoud Ahmadinejad. At least 36 people were killed in 2009, according to an official toll, while the opposition says 72 died.
(This story has not been edited by NDTV staff and is auto-generated from a syndicated feed.)