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Born into a distinguished family, Antonio Despuig y Dameto was the son of Ramón Despuig y Cotoner, Count of Montenegro and Montoro, and María Dameto y Sureda, daughter of the Marquises of Bellpuig. He pursued Humanities at the Colegio Nuestra Señora de Montesión of the Society of Jesus in Palma, subsequently earning doctorates in civil and canon law from the University of Luliana.

In 1774, Despuig was ordained and appointed canon of the church in Palma. By 1782, he traveled to Italy, where he experienced the devastating Calabria earthquake in 1783, later documenting the event in a notable account. Upon his return to Mallorca, he served as rector and vice-chancellor of the University of Luliana, lieutenant vicar general castrense, and judge conservator of the Order of St. John of Jerusalem. During this period, he also produced a comprehensive map of the island, published in 1785, which is widely considered the rarest, most beautiful and important map of Mallorca published in the 18th Century.

In 1785, King Carlos III appointed Despuig as Auditor of the Tribunal of the Rota for the Crown of Aragon. While in Rome at the papal court of Pius VI, he was a key advocate for the canonization of the Blessed Catalina Tomás, documenting her life in the process. In 1791, Despuig was named Bishop of Orihuela and returned to Spain the following year to assume his position. When the War of the Pyrenees broke out in 1793, Despuig was appointed administrator and later Archbishop of Valencia in 1795. Shortly after, he was transferred to the Archdiocese of Seville.

In 1797, Despuig, along with the Queen’s confessor Rafael Múzquiz, persuaded the Inquisitor General Francisco de Lorenzana to initiate an inquisitorial process against Prime Minister Manuel Godoy for bigamy and atheism. This led to their exile to Rome under the guise of accompanying Pope Pius VI, who was then imprisoned by French forces. During his exile, Despuig was bestowed the title of Latin Patriarch of Antioch by the Pope.

Despuig’s return to Spain was marred by courtly intrigues, forcing him to resign from the Archdiocese of Seville in favor of Luis María de Borbón y Vallabriga. In exchange, he received the archdeaconries of Valencia and Talavera in the Cathedral of Toledo and was appointed State Councillor and President of the Supreme Junta of Amortization.

In early 1800, Despuig was sent to Venice to participate in the conclave that elected Pope Pius VII. In 1803, Pius VII elevated him to Cardinal, with the title of San Calixto and appointed him Archpriest of the Basilica of Santa Maria Maggiore. From 1804 to 1807, he resided in his homeland before returning to a politically charged Rome, where he acted as pro-vicar in place of the exiled Cardinal Giulio Maria della Somaglia. In 1809, Despuig was with Pius VII when French forces abducted the Pope, leading to his own confinement in Paris.

Due to health issues, Despuig was permitted to travel to Lucca for treatment, where he died in 1813.  

Parallel to his ecclesiastical career, Despuig was an ardent art collector and patron. He was a member of the Society of Friends of the Country of the Kingdom of Mallorca, the Academy of San Fernando, and the Academy of San Lucas in Rome. He founded and supported the drawing school in Palma and the library and art gallery in the palace of the Counts of Montenegro. During his stays in Italy, he conducted numerous archaeological excavations on his property in Ariccia, amassing a significant collection of Roman sculptures and inscriptions.