After studying at the Pontifical Ecclesiastical Academy, he entered the Holy See’s diplomatic service and held posts in Lebanon, Venezuela, the First Section for Extraordinary Affairs of the Secretariat of State, France and the USA. Appointed titular Archbishop of Roselle on 24 February 1968, he was ordained on 12 May of that year and served as Apostolic Nuncio in Nicaragua and Honduras (1968-1973) and Zaire (1973-1977).
He was later Secretary of the Administration of the Patrimony of the Apostolic See (1977-1988) and Apostolic Nuncio in France (1988-1995). On 24 June 1995 he was appointed Pro-President of the Administration of the Patrimony of the Apostolic See. He later became President of the Administration of the Patrimony of the Apostolic See in February 1998.
President emeritus of the Administration of the Patrimony of the Apostolic See, 5 November 1998.
Pontifical Delegate of the Patriarchal Basilica of St. Francis of Assisi, 5 November 1998 until February 2006.
Created and proclaimed Cardinal by John Paul II in the consistory of 21 February 1998, of the Title of S. Agnese in Agone (St. Agnes in Agone, deaconry raised pro illa vice to presbyteral title on 1 March 2008).
Cardinal Lorenzo Antonetti died on 10 April 2013.