After the formation of the Italian Democratic Party (PD) in 2007, Mogherini was appointed to its executive committee by its founding chairman Walter Veltroni.

[13][16] Mogherini joined the Renzi Cabinet as Minister of Foreign Affairs, the third woman after Susanna Agnelli and Emma Bonino to hold this post.

Her first public engagement following her appointment was to meet, along with Italy's Defence Minister, the wives of Massimiliano Latorre and Salvatore Girone, the two Italian marines detained in India after the Enrica Lexie incident.

On 13 July 2014, the Financial Times among other European newspapers reported that her nomination proposal had been opposed by the Baltic states and several Central-European countries, including Latvia, Estonia, Lithuania, and Poland, where her stance towards Russia concerning the Russo-Ukrainian war was considered to be too soft.

Sweden, Ireland, Netherlands, and the United Kingdom also raised concerns, claiming the position should be filled by someone from the center-right and by a candidate from outside Germany, France, and Italy.

[citation needed] On 1 August 2014, Italian prime minister Matteo Renzi formally nominated her by letter to Juncker, the European Commission president-elect, as Italy's official candidate for Commissioner.

On the same day, the president Herman Van Rompuy announced that the European Council had decided to appoint Mogherini as its new High Representative, effective from 1 November 2014.

The group of commissioners involved in external relations—neighborhood and EU enlargement, trade, development, emergency and humanitarian aid, migration, energy, and transport—meets monthly, with Mogherini in the chair.

In 2015, Mogherini won praise for her role in negotiating the Joint Comprehensive Plan of Action (JCPOA), an international agreement on the nuclear program of Iran, and along with Iranian Foreign Minister Mohammad Javad Zarif was the one to announce the accord to the world.

[24] In 2016, she appointed chief negotiator Helga Schmid as Secretary General of the European External Action Service (EEAS), following the resignation of Alain Le Roy.

[25][26] Since 2015, Mogherini also began serving as a member of the European Commission’s High-level Group of Personalities on Defence Research chaired by Elżbieta Bieńkowska.

[28] In April 2017, Mogherini paid her first visit to India in an official capacity as European Union representative, discussing issues including climate change and anti-terrorism.

[31] In 2019, United Nations Secretary-General António Guterres appointed Mogherini as co-chair of the High Level-Panel on Internal Displacement, alongside Donald Kaberuka.

[40] Mogherini expressed that she wants the European Union to play a leading role in trying to restart Israeli-Palestinian peace talks after a U.S.-brokered process foundered in April 2014.

[41] In her capacity as European Union High Representative, she coordinated the last rounds of negotiations on Iran's nuclear programme, which led to an agreement on 14 July 2015.

[45] Mogherini issued a declaration on behalf of the European Union on 9 October 2019 stating: "In light of the Turkish military operation in north-east Syria, the EU reaffirms that a sustainable solution to the Syrian conflict cannot be achieved militarily.

"[46] In January 2015, Mogherini circulated a discussion paper among members of the Foreigns Affairs Council exploring a potential rapprochement with Russia, including a pathway to ease some sanctions against Russia after the start of the Russo-Ukrainian War and opening dialogue on a range of topics like visas and energy policy; the proposal drew a harsh response from the United Kingdom and Poland as the fighting intensified in eastern Ukraine.

[51] On 11 September 2018, Mogherini raised the issue of Xinjiang internment camps and the Chinese government's human rights abuses against the Uyghurs in European Parliament.