[7] Despite being considered a caretaker Prime Minister upon his appointment, during his time in office Gentiloni successfully delivered major reforms that had been delayed for many years, including the implementation of the advance healthcare directive and the passage of a new electoral law.

[33] The "Gentiloni Reform" bill of 12 October 2006, established the existence of a market dominance where a subject exceeded 45% of advertising sales and abolished the "integrated communication system" (SIC) introduced by the Gasparri Law.

The law also lowered the maximum advertising threshold for TV from 18% to 16%, to encourage redistribution, and provided for the transfer to digital of one network each for RAI and Mediaset by 2009, thus freeing up frequencies and imposing the obligation to sell (Europa 7 affair).

[29] As foreign minister, Gentiloni tried to trace an intermediate path for Italy in the scenario of multiple crises that surrounds it, from the wars in Libya and Syria to tensions with Russia.

[42] On 11 July 2015, a car bomb exploded outside the Italian consulate in the Egyptian capital Cairo, resulting in at least one death and four people injured; the Islamic State claimed responsibility.

In January 2015, he negotiated the release of Vanessa Marzullo and Greta Ramelli, two Italian students and activists who had been held hostage by Syrian terrorists for 168 days.

His recovered body showed signs of extreme torture like contusions and abrasions, extensive bruising from kicks, punches, and assault with a stick, more than two dozen bone fractures, a brain hemorrhage and a broken cervical vertebra, which ultimately caused death.

On 7 December 2016, Prime Minister Matteo Renzi announced his resignation, following the rejection of his proposals to overhaul the Senate in the 2016 Italian constitutional referendum.

[69][70] On 14 December 2017, the Parliament officially approved a law concerning the advance healthcare directive, better known as "living will", a legal document in which a person specifies what actions should be taken for their health if they are no longer able to make decisions for themselves because of illness or incapacity.

[73] The Catholic Church, led by Pope Francis, did not put up major objections to the living will law, saying that a balance needed to be struck with the prevention of excessive treatment or therapeutic obstinacy.

[86] In December 2017, the Gentiloni announced the peacekeeping mission which consists in the sending of 450 soldiers in Niger, to help the local forces in the fight against migrants' traffickers and Islamic terrorism.

The PD proposed a new electoral law called Mattarellum bis, better known as Rosatellum,[90] from the name of his main proponent Ettore Rosato, Democratic leader in the Chamber of Deputies.

[98] During his premiership, Gentiloni faced several challenging foreign policy situations, such as the European debt crisis, the civil war in Libya, the insurgency of the Islamic State (IS) in the Middle East.

[99] In April 2017, he was invited to the White House by President Trump, where the two leaders discussed the serious crisis caused by the civil wars in Libya and Syria, the tensions with Vladimir Putin's Russia and their key partnership against the Islamic terrorism.

While in office, Gentiloni built up a series of close relations with the Arab countries of the Persian Gulf, based especially on commercial agreements regarding oil and offshore producing concessions.

[106] Gentiloni visited the United Arab Emirates twice; the first one in November 2017 and the second one in March 2018, when he met in Abu Dhabi the crown prince Mohammed bin Zayed Al Nahyan.

[107] In May 2017, he had an official trip to China to meet President Xi Jinping and Prime Minister Li Keqiang, to discuss about the One Belt One Road Initiative, a development strategy proposed by the Chinese government that focuses on connectivity and cooperation between Eurasian countries.

[112] After some years of tensions due to the 2012 Enrica Lexie case, in which two Italian marines were arrested for killing two fishermen in Kerala, the two countries revived normal relations.

[115] During his term as foreign affairs minister and especially during his premiership, Gentiloni started a policy review which led to the creation of the Italy–Africa initiative, which includes renewable energy cooperation and a new package of development aid in fields stretching from health care to culture; counterterrorism has been a key part of his agenda, but the West Africa region is also important to stop the migration flows from there to Italy through North Africa, especially Libya.

On 24 November, Gentiloni visited Tunisia, where he met President Beji Caid Essebsi and Prime Minister Youssef Chahed, with whom he discussed the migrant crisis, the fight against terrorism and the Libyan Civil War.

[117] On 26 November he moved to Angola, where he had a bilateral meeting with President João Lourenço; the two leaders signed many economic deals between Eni and the Angolan Sonangol Group.

[118] On the following days Gentiloni went to Ghana to meet President Nana Akufo-Addo and visit Eni's plant named "John Agyekum Kufuor".

[127][128] After negotiations lasting several months, the League and the Five Star Movement agreed a programme for a coalition government led by the independent Giuseppe Conte; Gentiloni resigned as Prime Minister on 1 June 2018.

Gentiloni chose not to contest the leadership of the Democratic Party, instead remaining on the backbench within the Chamber of Deputies, where he frequently attacked the policies of Matteo Salvini as Interior Minister, particularly on immigration, Romani people and gun laws.

[139] On 10 September, Ursula von der Leyen announced that she would hand Gentiloni the role of Commissioner for Economy if he was successfully approved by the European Parliament.

[145] In early March 2020, Gentiloni was appointed by President von der Leyen to serve on the Commission's special task force to coordinate their response to the COVID-19 pandemic, which severely affected the European Union.

[146] The task force's plan consisted in the Next Generation EU program, an economic recovery package to support member states adversely impacted by the COVID-19 pandemic.

[147] In late 2024, United Nations Secretary-General António Guterres appointed Gentiloni to a group of experts to promote actionable policy solutions and galvanize political and public support required to resolve the developing world’s debt crisis, chaired by Mahmoud Mohieldin.

[155][156] These policies resulted in broad criticism from the left-wing Article One, PD's partners in the cabinet which later left the government's majority, as well as left-leaning intellectuals like Roberto Saviano and Gad Lerner.

[163] On 10 January 2017, after an official trip in Paris to meet President François Hollande, Gentiloni suffered an obstructed coronary artery and received an emergency angioplasty.