[1] On 12 April 1980, De Donatis was ordained a priest in the Church of San Domenico in Casarano in the Diocese of Nardò-Gallipoli by Bishop Antonio Rosario Mennonna.

[2] He became the spiritual director of the Pontifical Roman Major Seminary, where he served until 2003, when he was appointed a parish priest at the Basilica of San Marco Evangelista al Campidoglio in Rome[3] and an assistant for the National Association of Relatives of Clergy.

[6] De Donatis has maintained a connection with his hometown by leading spiritual exercises annually during the summer at the Crypt of the Crucifix in Casarano.

[8] In October 2013, Pope Francis, who had met De Donatis only once at that lunch, chose him to preach the 2014 Lenten spiritual exercises of the Roman Curia, an assignment that for fifty years had been given to a cardinal or well-known theologian.

De Donatis adopted his coat of arms with the episcopal motto "nihil caritate dulcius", a phrase taken from Saint Ambrose, which translates from the Latin as "nothing is sweeter than charity".

[12] In September 2016, De Donatis published Nulla è più dolce dell'amore (Nothing is Sweeter than Love), a collection of twenty reflections on the various forms of mercy as interpreted through the Bible.

[13] On 26 May 2017, Pope Francis appointed De Donatis the Vicar General of Rome and Archpriest of the Archbasilica of St. John Lateran,[14] elevating him as well to the rank of archbishop.

"[30] After testing positive for COVID-19, De Donatis entered the Agostino Gemelli University Policlinic with a fever on 30 March 2020; he had not been in physical contact with Pope Francis or visited the Vatican recently.

[32] Cardinal De Donatis was criticised by victims of Marko Rupnik's alleged spiritual and sexual abuse who expressed "bewilderment" with the Diocese of Rome's statement praising the art and theology centre he founded.

[38] Tierced inverted pall: in the first, red division of the field is contained a winged lion with a halo, with the head front-facing, while crouching and holding with its front legs in front of its chest a golden book bearing in black, capital letters PAX TIBI MARCE in four rows on the first side, and EVANGELISTA MEUS in four rows on the second side.

"[40] The lion of St. Mark the Evangelist, chosen in honor of the saint to whom is dedicated the parish he led before being appointed a bishop, stands on red, which is the color of love and blood.

The umbraculum, the symbol of the Bishop of Rome, over a blue background, representing the detachment from earthly values and the ascent of the soul to God.