The first phase of re-imposed US sanctions took effect on Tuesday under an executive order signed by President Donald Trump.
The sanctions financial transactions that involve US dollars, Iran's automotive sector, the purchase of commercial planes and metals including gold.
A second round of sanctions targeting Iran's oil sector and central bank are to be reimposed on November 4.
The stiff economic sanctions ratchet up pressure on Tehran despite statements of deep dismay from European allies, three months after Trump pulled the US out of the 2015 deal that limited Iran's nuclear activities.
Trump declared the landmark 2015 agreement had been "horrible," leaving the Iranian government flush with cash to fuel conflict in the Middle East.
As the sanctions loomed Monday, Trump said in a statement, "We urge all nations to take such steps to make clear that the Iranian regime faces a choice: either change its threatening, destabilizing behavior and reintegrate with the global economy, or continue down a path of economic isolation."
He warned that those who will not wind down their economic ties to Iran "risk severe consequences."
The Europeans did not like any of it.
Despite Trump's claims, the accord "is working and delivering on its goal" of limiting Iran's nuclear program, said a statement by European Union foreign policy chief Federica Mogherini and the foreign ministers of France, Germany and the United Kingdom.
The ministers said the Iran deal is "crucial for the security of Europe, the region and the entire world," and the European Union issued a "blocking statute" Monday to protect European businesses from the impact of the sanctions.
A senior administration official, briefing reporters under ground rules requiring anonymity, said the United States is "not particularly concerned" by EU efforts to protect European firms from the sanctions.
Iranian President Hassan Rouhani said that his country still can rely on China and Russia to keep its oil and banking sectors afloat. Speaking in a television interview, he also demanded compensation for decades of American "intervention" in Iran.
Months of uncertainty surrounding the sanctions have already further hurt Iran's economy. The country's rial currency has tanked, and the downturn has sparked protests across the nation.
US officials insisted the American government stands with the people of Iran and supports many of their complaints against their own government.
National security adviser John Bolton said Iran's leadership is on "very shaky ground," but he insisted economic pressure from the Trump administration is not an attempt at "regime change."
Secretary of State Mike Pompeo said sanctions are an important pillar in US policy toward Iran and will remain in place until the Iranian government radically changes course.
"They've got to behave like a normal country. That's the ask. It's pretty simple," said Pompeo, en route Sunday from a three-nation trip to Southeast Asia.
Israeli Prime Minister Benjamin Netanyahu, a firm foe of the Iranian government, said the sanctions symbolize "the determination to block Iran's regional aggression as well as its continuous plans to arm itself with nuclear weapons."
He called on the countries of Europe to join the US, saying, "The time has come to stop talking; the time has come to do."
The US has long designated Iran as the world's foremost state sponsor of terrorism, Pompeo noted Sunday, adding that Tehran cannot expect to be treated as an equal in the international community until it halts such activities.
He said that "there's no evidence today of a change in their behavior," and in the meantime "we're going to enforce the sanctions."
