Large numbers reportedly turned out in Rasht, in the north, and Kermanshah, in the west, with smaller protests in Isfahan, Hamadan and elsewhere.
The protests began against rising prices but have spiralled into a general outcry against clerical rule and government policies.
A small number of people have been arrested in Tehran, the capital.
They were among a group of 50 people who gathered in a city square, Tehran's deputy governor-general for security affairs told the Iranian Labour News Agency.
The demonstrations began in the north-eastern city of Mashhad - the country's second most-populous - on Thursday.
People there took to the streets to express anger at the government over high prices, and vented their fury against President Hassan Rouhani. Fifty-two people were arrested for chanting "harsh slogans".
The protests spread to other cities in the north-east, and and some developed into broader anti-government demonstrations, calling for the release of political prisoners and an end to police beatings.
On Friday, despite warnings from authorities, the demonstrations spread further to some of the biggest cities in the country.
They represent the most serious and widespread expression of public discontent in Iran since mass protests in 2009 that followed a disputed election, correspondents say.
What began as a protest against economic conditions and corruption has turned political.
Slogans have been chanted against not just Mr Rouhani but Supreme Leader Ayatollah Ali Khamenei, and clerical rule in general.
Demonstrators were reportedly heard yelling slogans like "The people are begging, the clerics act like God". Protests have even been held in Qom, a holy city home to powerful clerics.
There is also anger at Iran's interventions abroad. In Mashhad, some chanted "not Gaza, not Lebanon, my life for Iran", a reference to what protesters say is the administration's focus on foreign rather than domestic issues.