Persico entered the Capuchin Franciscan Order on 25 April 1839, and immediately after ordination was sent in November, 1846, to Patna, India. The vicar Apostolic, Anastasius Hartmann, made him his socius and confidant. In 1850 Persico accompanied Hartmann to Mumbai, when he was transferred to that vicariate, and assisted him in founding a seminary and establishing the "Bombay Catholic Examiner". At the time of the 1853 schism in Goa, then a part of the Portuguese Empire, the bishop sent Persico to Rome and London to lay the Catholic case before the Pope and the British Government. Persico was consecrated bishop on 8 March 1854, and nominated bishop-auxiliary to Bishop Hartmann; but the next year he was appointed visitor of the Vicariate of Agra, and afterwards vicar Apostolic of that district. During the Indian Mutiny he was several times in danger of his life. The anxieties of this period told upon his health and in 1860 he was compelled to return to Italy. An eyewitness account he wrote of the events in Agra was published in 1858. Sent in 1866 on a mission to the United States, he took part in the Council of Baltimore. On 20 March 1870, Persico was nominated Bishop of Savannah; but his health again failing, he resigned in 1873. In 1874 he was sent as Apostolic delegate to Canada; and in 1877 he was commissioned to settle the affairs of the Malabar schism. On 26 March 1879, he was appointed Bishop of Aquino in Italy; but in March, 1887, he was promoted to the titular Archbishopric of Tamiatha and sent as Apostolic delegate to Ireland to report upon the relations of the clergy with the political movement. He quickly saw that the question must be considered not merely in relation to present politics but also in relation to the history of Ireland, and he delayed his final report in order to consider the question in this broader aspect. Meanwhile, on 23 April 1888, the Congregation of the Holy Office declared that it was not lawful to make use of the Plan of Campaign and boycotting. In June 1888 Pope Leo XIII issued the encyclical "" reinforcing and defending this condemnation. "The promulgation of the Papal Rescript, condemning boycotting and the Plan of Campaign as grave offences against the moral law, took Mgr. Persico as much by surprise as it did Cardinal Manning; for both he and the Papal Delegate confidently expected that, in accordance with their joint suggestions, the condemnation of the immoral methods of the League would have been pronounced not directly by the Holy See, but by the Irish Episcopate." Persico returned to Rome much disappointed. He was at once nominated Vicar of the Vatican Chapter. Persico later commented, "I had no idea that anything had been done about Irish affairs, much less thought that some questions had been referred to the Holy Office, and the first knowledge I had of the decree was on the morning of the 28th April, when I received the bare circular sent me by Propaganda. I must add that had I known of such a thing I would have felt it my duty to make proper representations to the Holy See". On 16 January 1893, he was created cardinal priest of the title of St. Peter in Chains. Persico died on December 7, 1895.
