In July 2014, given the large number of Italian MEPs belonging to the S&D group following the European election, 2014, the European Council considered her as a candidate for the position of High Representative of the Union for Foreign Affairs and Security Policy, in Jean-Claude Juncker's new European Commission. On the 13th July 2014, the Financial Times among other European newspapers reported that her nomination proposal had been opposed by some eastern European countries, including Latvia, Estonia, Lithuania and Poland, where her stance towards Russia concerning the Ukrainian crisis was considered to be too soft.
Nonetheless, on 2 August 2014, Italian Prime Minister Matteo Renzi formally nominated her by letter to EC President-elect Jean-Claude Juncker, as Italy's official candidate for EU Commissioner.
On 30 August, Europe's socialist Prime Ministers met prior to the convening of the European Council, at which she received the approval of the Party of European Socialists. On the same day the President Herman Van Rompuy announced that the European Council had decided to appoint the Italian Minister as its new High Representative, effective from 1 November 2014.
At her first press conference she declared her efforts will be devoted to establishing discussions between Russia and Ukraine to solve the crisis between the two countries.
In 2015, Mogherini won praise for her role in negotiating the Joint Comprehensive Plan of Action, 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.