He was born at Sonnino near Terracina and was educated for the priesthood, but, after taking minor orders, gave up the idea of becoming a priest, and chose an administrative career. Created secular prelate, he was sent as apostolic delegate to Viterbo in 1836, where he early manifested his reactionary tendencies in an attempt to stamp out Liberalism. In 1839 he was transferred to Macerata. In 1840 he was ordained a deacon. Recalled to Rome in 1841 by Pope Gregory XVI, he entered the offices of the Secretariat of State, but four years later was appointed pontifical treasurer-general. Created cardinal (June 11, 1847), one of the last cardinal deacons in deacon's orders, he was chosen by Pius IX to preside over the council of state entrusted with the drafting of a constitution for the Papal States.
On March 10, 1848, Antonelli became premier of the first constitutional ministry of Pius IX. Upon the collapse of his cabinet when liberals resigned in protest again papal public refusal to participate in a war of national liberation, 29 April 1848, Antonelli created for himself the governorship of the sacred palaces in order to retain constant access to and influence over the pope. After the assassination of Pellegrino Rossi (November 18, 1848) he arranged the flight of Pius IX to Gaeta. In that year, the Papal States were overthrown by Liberals and replaced by a Roman Republic, only to be restored to the pope in 1849 by force of French and Austrian arms, called in at Antonelli's request.
Notwithstanding promises to the powers, upon returning to Rome (April 12, 1850) Antonelli restored absolute government and disregarded the conditions of the surrender by wholesale imprisonment of Liberals. In 1855 he narrowly escaped assassination. As an ally of Ferdinand II of the Two Sicilies, from whom he had received an annual subsidy, he attempted, after 1860, to facilitate Ferdinand's restoration by fomenting brigandage on the Neapolitan frontier. To the overtures of Ricasoli in 1861, Pius IX, at Antonelli's suggestion, replied with the famous "Non possumus," but subsequently (1867) accepted, too late, Ricasoli's proposal concerning ecclesiastical property.
After the September Convention of 1864, Antonelli organized the Legion of Antibes to replace French troops in Rome, and in 1867 secured French aid against Garibaldi's invasion of papal territory. Upon the reoccupation of Rome by the French after the battle of Mentana on 3 November 1867, Antonelli again ruled supreme, but after the entry of the Italians in 1870 was obliged to restrict his activity to the management of foreign relations. With the Pope's approval, he wrote the letter requesting the Italians to occupy the Leonine City (in which the Italian government had intended to allow the pope to keep his temporal power), and obtained from the Italians payment of the Peter's pence (5,000,000 lire) remaining in the papal exchequer, as well as 50,000 scudi, the only installment of the Italian allowance (subsequently fixed by the Law of Guarantees, March 21, 1871) ever accepted by the Holy See.
By the nature of the post he occupied, from 1850 until his death Antonelli had little to do with questions of dogma and Church discipline, although his was the signature on circulars addressed to the Powers transmitting the Syllabus of Errors (1864) and the acts of the First Vatican Council (1870).
His activity was devoted almost exclusively to the struggle between the papacy and the Italian Risorgimento. He died on 6 November 1876.
At Antonelli's death the papal finances were found to be in disorder, with a deficit of 45,000,000 lire. Antonelli's personal fortune, accumulated during office, was considerable, and was bequeathed almost entirely to members of his family. To the Church he left little and to the pope only a souvenir.
Although it did not prevent Pius IX's beatification, some observers believe that Antonelli's notoriety might be enough to prevent his canonization. Antonelli was one of the last deacons to be created a cardinal before Pope Benedict XV decreed in 1917 that all cardinals must be ordained priests.1850: Grand Cross in the Legion of Honour.
No cardinal eligible to participate in a papal conclave has gone as long as Antonelli–29 years–without doing so. Roger Etchegaray was a cardinal for a longer period without participating in a conclave, but he was only eligible to do so for about 23 years. In both Antonelli's and Etchegaray's cases, their non-participation in conclaves was not by choice as there was no conclave for them to attend. No papal death or resignation triggering a conclave occurred during Antonelli's cardinalate while in Etchegaray's cardinalate, the conclaves of 2005 and 2013 occurred when he was no longer eligible to participate.
He appears as a character in the movie Li chiamarono... briganti! (1999), interpreted by Giorgio Albertazzi.