According to Andrija Zmajević's chronicle, his father originated from the Bay of Kotor (modern-day Montenegro) and was born in Bjelske Kruševice, a village near Bijela, into the Šišić family, possibly called Slavjan. The theory that he comes from the Svilanović family is unfounded. As a child, he served in a Catholic monastery in Kotor, where he converted from Serbian Orthodoxy to Roman Catholicism and was subsequently taken to Italy by an Italian friar. He settled in Ancona, where he married and had Felice Peretti (Srećko Perić in modern Serbo-Croat). Not much else is recorded about Peretti's father, but when Felice eventually became Pope Sixtus V, he rebuilt the church of Saint Jerome in Rome (finished in 1589), to be used specifically for the people who spoke the Illyrian language. He also established a college of eleven Slavonic clerics in his papal bull Sapientiam Sanctorum of August 1, 1589. This was later transformed into the Pontifical Croatian College of St. Jerome.
At an early age he entered a Franciscan monastery at Montalto delle Marche and was known as Felice di Montalto. He soon gave evidence of rare ability as a preacher and a dialectician. About 1552 he was noticed by Cardinal Rodolfo Pio da Carpi (1500–64), protector of his order, Ghislieri (later Pope Pius V) and Caraffa (later Pope Paul IV), and from that time his advancement was assured. He was sent to Venice as inquisitor general, but was so severe and carried matters with such a high hand that he became embroiled in quarrels. The government asked for his recall in 1560.
After a brief term as procurator of his order, he was attached to the Spanish legation headed by Ugo Boncampagni (later Pope Gregory XIII) in 1565, which was sent to investigate a charge of heresy levelled against Archbishop Bartolome Carranza of Toledo. The violent dislike he conceived for Boncampagni exerted a marked influence upon his subsequent actions. He hurried back to Rome upon the accession of Pius V (1566–72), who made him apostolic vicar of his order, and, later (1570), cardinal.
During the pontificate of his political enemy Gregory XIII (1572–85) the Cardinal Montalto, as he was generally called, lived in enforced retirement, occupied with the care of his property, the Villa Montalto, erected by Domenico Fontana close to his beloved church on the Esquiline Hill, overlooking the Baths of Diocletian. The first phase (1576–80) was enlarged after Peretti became pope and could clear buildings to open four new streets in 1585–1586. The villa contained two residences, the Palazzo Sistino or "di Termini" ("of the Baths") and the casino, called the Palazzetto Montalto e Felice. Displaced Romans were furious. The decision to build the central pontifical railroad station (begun in 1869) in the area of the Villa marked the beginning of its destruction.
The Cardinal Montalto's other concern was with his studies, one of the fruits of which was an edition of the works of Ambrose. As pope he personally supervised an improved edition of Jerome's Vulgate-- which is "as splendid a translation of the Bible into Latin as the King James version is into English. Though not neglecting to follow the course of affairs, but carefully avoiding every occasion of offence. This discreetness contributed not a little to Sixtus V's election to the papacy on April 24, 1585; but the story of his having feigned decrepitude in the conclave, in order to win votes, is a pure invention. One of the things that commended his candidacy to certain Cardinals was his physical vigour, which seemed to promise a long pontificate.
The terrible condition in which Pope Gregory XIII had left the ecclesiastical states called for prompt and stern measures. Against the prevailing lawlessness Sixtus V proceeded with an almost ferocious severity, which only extreme necessity could justify. Thousands of brigands were brought to justice: within a short time the country was again quiet and safe. Next Sixtus V set to work to repair the finances. By the sale of offices, the establishment of new "Monti" and by levying new taxes, he accumulated a vast surplus, which he stored up against certain specified emergencies, such as a crusade or the defence of the Holy See. Sixtus V prided himself upon his hoard, but the method by which it had been amassed was financially unsound: some of the taxes proved ruinous, and the withdrawal of so much money from circulation could not fail to cause distress.
Immense sums, however, were spent upon public works, in carrying through the comprehensive planning that had come to fruition during his retirement, bringing water to the waterless hills in the Acqua Felice,feeding twenty-seven new fountains; laying out new arteries in Rome, which connected the great basilicas, even setting his engineer-architect Domenico Fontana to replan the Colisseum as a silk-spinning factory housing its workers. The Pope set no limit to his plans; and what he achieved in his short pontificate, carried through always at top speed, is almost incredible; the completion of the dome of St. Peter's; the loggia of Sixtus in the Basilica di San Giovanni in Laterano; the chapel of the Praesepe in Santa Maria Maggiore; additions or repairs to the Quirinal, Lateran and Vatican palaces; the erection of four obelisks, including that in St Peter's Square; the opening of six streets; the restoration of the aqueduct of Septimius Severus ("Acqua Felice"); the integration of the Leonine City in Rome as XIV rione (Borgo); besides numerous roads and bridges, he sweetened the city air by financing the Pontine Marshes. Good progress was made with more than 9,500 acres reclaimed and opened to agriculture and manufacture; the project was abandoned upon his death.
But Sixtus V had no appreciation of antiquities, which were employed as raw material to serve his urbanistic and Christianising programs: Trajan's Column and the Column of Marcus Aurelius (at the time misidentified as the Column of Antoninus Pius) were made to serve as pedestals for the statues of SS Peter and Paul; the Minerva of the Capitol was converted into an emblem of Christian Rome; the Septizonium of Septimius Severus was demolished for its building materials.
Sixtus V agreed to renew the excommunication of Queen Elizabeth I of England (1558–1603), and to grant a large subsidy to the Armada of King Philip II, but, knowing the slowness of Spain, would give nothing till the expedition should actually land in England. In this way he was saved his crown millions, and spared the reproach of having taken futile proceedings against what Roman Catholics viewed as the heretic Queen. This excommunication which Catholics of the day considered richly deserved, and there is extant a proclamation to justify it, which was to have been published in England if the invasion had been successful. It was signed by Cardinal Allen, and is entitled "An Admonition to the Nobility and Laity of England". It was intended to comprise all that could be said against Queen Elizabeth I, and the indictment is therefore fuller and more forcible than any other put forward by the religious exiles, who were generally very reticent in their complaints. Allen also carefully consigned his publication to the fire, and we only know of it through one of Elizabeth's ubiquitous spies, who had previously stolen a copy.
Sixtus V excommunicated Henry of Navarre (future Henry IV of France), and contributed to the Catholic League, but he chafed under his forced alliance with Philip II, and looked for escape. The victories of Henry and the prospect of his conversion to Catholicism raised Sixtus V's hopes, and in corresponding degree determined Philip II to tighten his grip upon his wavering ally. The Pope's negotiations with Henry's representative evoked a bitter and menacing protest and a categorical demand for the performance of promises. Sixtus V took refuge in evasion, and temporized until death relieved him of the necessity of coming to a decision (August 27, 1590).