On March 10, 1848, Antonelli became premier of the first constitutional ministry of Pius IX. Upon the collapse of his cabinet when liberals resigned following the publicly renounced Papal participation in the 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, he restored absolute government upon returning to Rome (April 12, 1850) and violated the conditions of the surrender by wholesale imprisonment of Liberals. In 1855 he narrowly escaped assassination. As 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, 3 November 1867, Antonelli again ruled supreme, but upon the entry of the Italians in 1870 was obliged to restrict his activity to the management of foreign relations. He wrote, with papal approval, 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 first and only installment of the Italian allowance (subsequently fixed by the Law of Guarantees, March 21, 1871) ever accepted by the Holy See.
At Antonelli's death the Vatican finances were found to be in disorder, with a deficit of 45,000,000 lire. His 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 trifling souvenir. From 1850 until his death he interfered little in affairs of dogma and church discipline, although he addressed to the powers circulars enclosing the Syllabus of Errors (1864) and the acts of the First Vatican Council (1870).
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 1918 that all cardinals must be ordained priests.