Concerning international negotiations with respect to Iran's nuclear program, he said "that the present difficulties can and must be overcome through diplomatic channels, making use of all the means that diplomacy has at its disposal and considers necessary to eliminate all the elements which objectively impede mutual trust.

"[5] Parolin represented the Vatican in a variety of sensitive assignments, including trips to North Korea and Vietnam[6] as well as the 2007 Annapolis Conference on the Middle East convened by the Bush administration to revive Israeli-Palestinian peace talks.

[2] During his time as undersecretary Parolin scored some significant breakthroughs, such as cementing ties between the Holy See and Vietnam,[8] re-establishing direct contact with Beijing in 2005 and helping secure the liberation of 15 British navy personnel captured by Iranian forces in the Persian Gulf in April 2007.

[15] Parolin became Francis’ first cardinal when he was made Cardinal-Priest of Santi Simone e Giuda Taddeo a Torre Angela at a papal general consistory on 22 February 2014.

[17] In 2014 Venezuela's President Nicolas Maduro invited Cardinal Parolin to mediate talks between his government and opposition in hopes of stemming violence that has killed dozens in the nation's worst unrest in a decade.

He asked that Parolin, a former nuncio to Venezuela, be named a "good faith witness" to a dialogue the parties had agreed upon after two months of protests.

Henrique Capriles, the opposition's two-time presidential candidate who narrowly lost an election to Maduro the year before, confirmed he would take part in the discussions.

The Vatican said they discussed the U.S. commitment to closing the facility and that Parolin expressed the Holy See's desire that "favourable attention be paid to finding adequate humanitarian solutions for current inmates".

He said that "the president of the United States has already thanked the Pope for the support he has given to this important step" and said: "Holy See diplomacy is always there, to help to build bridges".

Parolin spoke about the chaos there after ISIS beheaded 21 Egyptian Coptic Christians, describing the incident as "terrifying" and the situation "grave".

Following the resignation of Marie Collins from the Pontifical Commission for the Protection of Minors, Parolin said she quit because she wanted to "shake the tree" in the Vatican.

Collins said some members of the Church's administration, the Roman Curia, have hindered and blocked the commission's efforts, naming the Congregation for the Doctrine of the Faith.

[32] Parolin told Italy's La Stampa the flow of migrants and refugees into Europe is testing "the spirit of solidarity and subsidiarity" of the European Union, and acknowledged the large number of people fleeing to the continent poses a security problem.

[41] In October 2018, Parolin said that Paul VI rejected a version of Humane Vitae that "was limited to a rigorous reaffirmation of doctrine to which Christians and all people were asked to adhere docilely and without reservation".

"We signed this agreement to help advance religious freedom, to find normalization for the Catholic community there, and then for all other religions to have space and a role to play in society which is recognized," Parolin told journalists on 3 April.

Steve Bannon said that he might lead a lawsuit to compel the Holy See to release the text of the deal under the terms of the 1961 Vienna Convention on Diplomatic Relations.

On 21 September 2020, at the end of its five-year mandate a new board makeup was announced, omitting the Secretary of State, thus Pope Francis did not confirm Parolin in the role.

[48] In May 2022, Cardinal Parolin stated that supplying weapons to Ukraine to help it defend itself is morally legitimate, "There is a right to armed defence in the case of aggression.

The Israeli Embassy to the Holy See called his remarks, “a deplorable declaration.”[54] Parolin has said both parties to a deal with Chinese authorities on episcopal appointments hope that it will be renewed for a third time when it expires in late 2024.

[55] Cardinal Parolin visited Ukraine to close a popular Marian pilgrimage, and met with civil and ecclesial authorities amid the Holy See’s continued push for peace.

[56][57] At COP 29 in November 2024 it was reported that Cardinal Parolin aligned with Saudi Arabia, Russia, Iran, and Egypt to obstruct a deal which would have provided support, including financial help, for women at the forefront of climate change according to Colombia’s environment minister.