During his tenure as foreign minister, Zarif led the Iranian negotiation with P5+1 countries which produced the Joint Comprehensive Plan of Action on 14 July 2015,[8] lifting the economic sanctions against Iran on 16 January 2016.

He served as an advisor and senior advisor to the Foreign Minister, Deputy Foreign Minister in Legal and International affairs, member of the UN Eminent Persons Group on Dialogue Among Civilizations, Head of the UN Disarmament Commission in New York, and Vice President for International Affairs of the Islamic Azad University.

[17] As a junior diplomat Zarif was involved in negotiations to win the release of U.S. hostages held by pro-Iranian gunmen in Lebanon, according to the memoirs of former United Nations envoy Giandomenico Picco.

Even though the United States did not make a promised reciprocal goodwill gesture at the time, Zarif remained committed to improving ties.

[27] Zarif, during his time at the UN, held private meetings with a number of Washington politicians, including the then-Senators Joseph Biden and Chuck Hagel.

[29] In 2007, Zarif was a headline speaker at an American Iranian Council conference in New Brunswick, New Jersey including Chuck Hagel, Dennis Kucinich, Nicholas Kristof, and Anders Liden to discuss Iranian-American relations, and potential ways to increase dialogue and avoid conflict.

[33] On 5 September 2013, in an exchange prompted by his Rosh Hashanah greeting on Twitter, Zarif said that Iran does not deny the Holocaust, distancing the government from the often belligerent stances by former President Mahmoud Ahmadinejad.

[39] Talks between senior American, Iranian and European diplomats in October 2014 produced no breakthrough agreement on curbing Iran's nuclear program, but officials said they still aimed to reach a deal by the 24 November deadline.

A senior State Department official characterized each step of progress in the talks as "chipping away" at complex, technical differences, with virtually every sentence requiring an appendix of further explanation.

"We continue to make progress, but there is still a substantial amount of work to be done," said the official, who spoke on the condition of anonymity to discuss the difficult and secretive negotiations.

[40] Zarif and Kerry conferred, ahead of a fresh round of negotiations between Iran and six world powers in Geneva, on settling their 12-year standoff over Tehran's nuclear ambitions.

[41] In February, Zarif said that Iran did not favor another extension of the talks on limiting its nuclear program and expected economic sanctions to be quickly lifted if an accord was reached.

On 21 November it was reported by Iranian negotiators that progress was being made in talks in Geneva with world powers, expressing hope to bridge differences and sign an elusive deal over Tehran's nuclear drive.

In statements carried by Iranian media after a one-hour meeting with Baroness Ashton, Zarif said "Differences of opinion remain and we are negotiating over them.

[8] On 29 April 2015, while appearing on The Charlie Rose Show, Zarif was asked about the detention of Jason Rezaian, the Washington Post reporter held in Iran for the past nine months.

]"[45] Zarif condemned U.S. involvement in the Saudi Arabian-led intervention in Yemen, saying the United States should be held "accountable for crimes against humanity".

[53] Zarif defended Islamic Republic's moral policies at a joint press conference with German Foreign Minister Heiko Maas in 2019.

After greetings in honor of Iranian Women's and Mothers' day, he wrote I am apologising [to] you (wholeheartedly) for my (inability to continue my service and any) shortcomings in the past years during my time as foreign minister...

[55][56] An aide said that one of the reasons for Zarif's resignation was anger over his exclusion that day from meetings with Syrian president Bashar al-Assad, who was visiting Tehran.

"[60] On 25 April 2021, The New York Times published content from a leaked audiotape of a three-hour taped conversation between economist Saeed Laylaz and Zarif.

The taped conversation was connected to an oral history project, "In the Islamic Republic the military field rules," that documents the work of Iran's current administration.

However, Zarif resigned shortly afterwards due to disagreements over the composition of Pezeshkian's cabinet, saying that the latter had failed to fulfill his promises to include more women, young people and ethnic groups.

[80][81] According to a poll conducted by Information and Public Opinion Solutions LLC (iPOS) in March 2016, Zarif was the most popular political figure in Iran with 76% approval and 7% disapproval ratings.