The Treasury Department said it was imposing sanctions on Zarif for acting on behalf of Iranian Supreme Leader Ayatollah Ali Khamenei.
"Javad Zarif implements the reckless agenda of Iran's Supreme Leader, and is the regime's primary spokesperson around the world," Treasury Secretary Steven Mnuchin said in a statement.
Zarif brushed off the sanctions on Twitter, saying the US move indicates Washington sees him as a "threat".
"It has no effect on me or my family, as I have no property or interest outside of Iran," he said.
Javad Zarif✔@JZarif
The US' reason for designating me is that I am Iran's "primary spokesperson around the world"
Is the truth really that painful?
It has no effect on me or my family, as I have no property or interests outside of Iran.
Thank you for considering me such a huge threat to your agenda.
9:33 PM - Jul 31, 2019
Iran's Foreign Ministry Spokesman Abbas Mousavi added on Twitter: "The peak of stupidity and inconsistency of America's leaders is at a point where they don't recognise Dr Zarif as being influential in Iran's policy but with the ultimate ignorance they sanction him! The Americans have a strong fear of the logic of Dr Zarif and his negotiating skills."
The Trump administration said it would make decisions on whether to grant Zarif a travel visa, including for trips to the United Nations, on a case by case basis, holding open the possibility that he might attend the annual UN General Assembly in September. Zarif last visited the UN in New York earlier this month.
A senior US official reiterated that Trump was open to talks with Iran, but said the administration did not consider Zarif to be a key decision-maker.
The highly unusual action of penalising the top diplomat of another country comes a month after President Donald Trump signed an executive order placing sanctions on Iran's supreme leader, Ayatollah Ali Khamenei.
Tensions have escalated between the two countries since Trump withdrew the US from the 2015 nuclear deal and reimposed sanctions on Iran.
Fears of a direct US-Iranian conflict have risen since May with several attacks on oil tankers in the Gulf, Iran's downing of a US surveillance drone, and a plan for US air raids on Iran last month that Trump called off at the last minute.
Iran may cut commitments
On Wednesday, Zarif said that Iran may cut its commitments under the international nuclear deal further unless European partners move to protect it from US sanctions by ensuring it can sell oil and receive income.
Zarif also said Tehran was ready to negotiate with rival Saudi Arabia. He said, however, US Secretary of State Mike Pompeo was not welcome in Iran.
"You don't need to come to Iran," Zarif told reporters, addressing Pompeo. He called Pompeo's offer to visit Tehran and address the Iranian people a "hypocritical gesture".
On Monday, Pompeo tweeted: "We aren't afraid of [Zarif] coming to America where he enjoys the right to speak freely. Are the facts of the [Khamenei] regime so bad he cannot let me do the same thing in Tehran?" he said, referring to Supreme Leader Ali Hosseini Khamenei.
"What if his people heard the truth, unfiltered, unabridged?"
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