He was born in Gravina in Puglia, the eldest of six sons of Ferdinando III Orsini, duke of Gravina, and Giovanna Frangipani della Tolfa, from Toritto. A member of the Orsini of Rome, he was the third and last member of that family to become Pope. At the age of eighteen he resigned his inheritance and entered the Dominican Order where he received the name of "Vincenzo Maria". He was ordained to the priesthood in February 1671.
Through the influence of his family, he was named, by Pope Clement X, Cardinal-Priest of San Sisto on 22 February 1672 (allegedly against his will). He also lectured in philosophy at Brescia. Later he was bishop of Manfredonia, bishop of Cesena and then archbishop of Benevento. After an earthquake in 1688 and another in 1702 he organized relief efforts for the victims. He remained a close friend of a local mystic, Serafina di Dio.
On 4 June 1724, he was crowned by Benedetto Pamphili, the cardinal protodeacon. On the following 24 September, he took possession of the Basilica of St. John Lateran.
With the papal bull Pretiosus dated May 26, 1727 Benedict XIII granted to all Dominicans major houses of study and in particular to the Roman College of St. Thomas, the Future Pontifical University of St. Thomas Aquinas, Angelicum the right of conferring academic degrees in theology to students outside the Order.
Through the process of equipollent canonization, Benedict XIII canonized Pope Gregory VII on 24 May 1728. He conferred sainthood upon Agnes of Montepulciano in 1726, Aloysius Gonzaga on 31 December 1726, Boris of Kiev in 1724, Francis Solano on 27 March 1726, Gleb in 1724, James of the Marches and Turibius of Mogroveio on 10 December 1726, John of Nepomuk on 19 March 1729, John of the Cross and Peregrine Laziosi on 27 December 1726, Margaret of Cortona on 16 May 1728 and Serapion of Algiers on 14 April 1728.
The pope named Saint Peter Chrysologus as a Doctor of the Church in 1729.
After the next papal election elevated Pope Clement XII to the pontificate, Clement excommunicated Benedict XIII's corrupt deputy, Cardinal Coscia. Coscia fled Rome and his punishment, but was later restored and took part in the conclaves of 1730 and 1740.
The process for his beatification was opened in Tortona in 1755 under Pope Benedict XIV but it did not at all advance and so was stalled. On 21 February 1931, also in Tortona, the process was revitalized but the presumed doubts about the morality of the late pontiff's Cardinal Secretary of State, Cardinal Niccolò Coscia, caused its closing in 1940.
The process was reopened on 17 January 2004. The official diocesan process commenced in Rome in early 2012 and the official opening of that process was held in the Basilica of Saint John Lateran, presided by Cardinal Agostino Vallini. The diocesan phase for the beatification process concluded on 24 February 2017 at the Basilica of Saint John Lateran with Cardinal Vallini celebrating the conclusion of the inquest. He now has the posthumous title of Servant of God.
Pope Benedict XIV would later say of Benedict XIII: "We respectfully love that pontiff who backed his carriage rather than dispute the passage with a Cartman." On that occasion Benedict XIII had exclaimed to his coachman: "Non ci far impicci"—"Do not involve us in a quarrel." On the other hand, this anonymous satirical comment on Benedict XIII's death was posted at the Pasquino: