Cardinal De Paolis was born in Sonnino, Italy on September 19, 1935.

He made his profession as a  member of Congregation of the Missionaries of St. Charles on October 4, 1958, and was ordained a Priest with the order on March 18, 1961.

On December 30, 2003 he was appointed Titular Bishop of Thelepte, and Secretary of the Apostolic Signatura. His ordination as Bishop took place on February 21, 2004. Just a few years later, on April 12, 2008, he was appointed Titular Archbishop of Thelepte and President of the Prefecture for the Economic Affairs of the Holy See.

On November 20, 2010 he was appointed Cardinal-Deacon of Gesù Buon Pastore alla Montagnola and elevated to Cardinal. His installation took place on May 15, 2011.

He retired from his position as President of the Prefecture for the Economic Affairs of the Holy See on September 21, 2011.