Cardinal Dominique Mamberti was born in Marrakech, Morocco, on March 7, 1952, to French parents. After studying law in Strasbourg and completing postgraduate courses at Paris II, earning degrees in public law and political science, he entered the French Pontifical Seminary in Rome. He was ordained a priest for the Diocese of Ajaccio on September 20, 1981. He continued his studies at the Pontifical Gregorian University, where he had already studied philosophy and theology, obtaining a degree in canon law.

He entered the diplomatic service of the Holy See on March 1, 1986, serving in the pontifical representations in Algeria, Chile, at the United Nations in New York, in Lebanon, and in the Section for Relations with States of the Secretariat of State. On May 18, 2002, Pope John Paul II appointed him titular archbishop of Sagone and apostolic nuncio to Sudan and apostolic delegate to Somalia. He received episcopal ordination on July 3 of the same year from Cardinal Angelo Sodano. On February 19, 2004, he was also appointed apostolic nuncio to Eritrea.

On September 15, 2006, Pope Benedict XVI called him back to the Secretariat of State to serve as Secretary for Relations with States, a position in which he was confirmed by Pope Francis on August 31, 2013. In this role, he led delegations to numerous international meetings and conferences, including the UN General Assembly and the OSCE ministerial councils, and signed various agreements on behalf of the Holy See.

On November 8, 2014, he was appointed Prefect of the Supreme Tribunal of the Apostolic Signatura. On April 28, 2015, he was also appointed President of the Commission for Lawyers. Pope Francis created and proclaimed him Cardinal in the Consistory of February 14, 2015, assigning him the Deaconry of Santo Spirito in Sassia.

He is a member of the Council of the Second Section of the Secretariat of State, as well as of the Dicasteries for Divine Worship and the Discipline of the Sacraments, the Causes of Saints, Evangelization, and Legislative Texts.