Savonarola was born in Ferrara, the capital of an independent Duchy in Emilia-Romagna, northern Italy. According to another source, he was born at Occhiobello, 7 km from Ferrara. He was born into a respected and affluent family that had originally resided in Padua. In his youth he studied the Bible, St. Thomas Aquinas and Aristotle. Savonarola initially studied at the University of Ferrara, where he appears to have taken an advanced Arts degree. His stance against morally corrupt clergy was initially manifested in his poem on the destruction of the world entitled De Ruina Mundi (On the Downfall of the World), written at the age of 20. It was at this stage that he also began to develop his expression of moral conscience, and in 1475 his poem De Ruina Ecclesiae (On the Downfall of the Church) displayed his contempt of the Roman Curia by terming it 'a false, proud archaic wench'.

Savonarola became a Dominican friar in 1475, during the Italian Renaissance, and entered the monastery of San Domenico in Bologna. He immersed himself in theological study, and in 1479 transferred to the monastery of Santa Maria degli Angeli. Finally in 1482 the Order dispatched him to Florence, the ‘city of his destiny’. Savonarola was lambasted for being ungainly, as well as being a poor orator. He made no impression on Florence in the 1480s, and his departure in 1487 went unnoticed. He returned to Bologna where he became 'master of studies’.

Savonarola returned to Florence in 1490 at the behest of Count Pico della Mirandola. There he began to preach passionately about the Last Days, accompanied by testimony about his visions and prophetic announcements of direct communications with God and the saints. Such fiery preaching was not uncommon at the time, but a series of circumstances quickly brought Savonarola great success. The first disaster to give credibility to Savonarola’s apocalyptic message was the Medici family's weakening grip on power owing to the French-Italian wars. The flowering of expensive Renaissance art and culture paid for by wealthy Italian families now seemed to mock the growing misery in Italy, creating a backlash of resentment among the people. The second disaster was the appearance of syphilis (or the “French pox”). Finally, the year 1500 was approaching, which may have brought about a mood of millennialism. In minds of many, the Last Days were impending and Savonarola was the prophet of the day. His Church of San Marco was crowded to over-flowing during his celebration of Mass and at his sermons. Savonarola was a preacher, not a theologian. He preached that Christian life involved being good and practicing the virtues, rather than religious pomp and ceremony. He did not seek to make war on the Church of Rome. Rather, he wanted to correct the transgressions of worldly popes and secularized members of the Papal Curia.

Lorenzo de Medici, the previous ruler of Florence and patron of many Renaissance artists, was also a former patron of Savonarola. Eventually, Lorenzo and his son Piero de Medici became targets of Savonarola’s preaching. After Charles VIII of France invaded Florence in 1494, the ruling Medici were overthrown and Savonarola emerged as the new leader of the city, combining in himself the role of secular leader and priest. He set up a republic in Florence. Characterizing it as a “Christian and religious Republic,” one of its first acts was to make sodomy, previously punishable by fine, into a capital offence. Homosexuality had previously been tolerated in the city, and many homosexuals from the elite now chose to leave Florence. His chief enemies were the Duke of Milan and Pope Alexander VI, who issued numerous restraints against him, all of which were ignored.

In 1497, he and his followers carried out the Bonfire of the Vanities. They sent boys from door to door collecting items associated with moral laxity: mirrors, cosmetics, lewd pictures, pagan books, immoral sculptures (which he wanted to be transformed into statues of the saints and modest depictions of biblical scenes), gaming tables, chess pieces, lutes and other musical instruments, fine dresses, women’s hats, and the works of immoral and ancient poets, and burnt them all in a large pile in the Piazza della Signoria of Florence. Many fine Florentine Renaissance artworks were lost in Savonarola’s notorious bonfires — including paintings by Sandro Botticelli, which he is alleged to have thrown into the fires himself. Florence soon became tired of Savonarola because of the city’s continual political and economic miseries partially derived from Savonarola's opposition to trading and making money. When a Franciscan preacher challenged him to a trial by fire in the city centre and he declined, his following began to dissipate.

During his Ascension Day sermon on May 4, 1497, bands of youths rioted, and the riot became a revolt: dancing and singing taverns reopened, and men again dared to gamble publicly. On May 13, 1497, the rigorous Father Savonarola was excommunicated by Pope Alexander VI, and in 1498, Alexander demanded his arrest and execution. On April 8, a crowd attacked the Convent of San Marco. A bloody struggle ensued, during which several of Savonarola’s guards and religious supporters were killed. Savonarola surrendered along with Fra Domenico da Pescia and Fra Silvestro, his two closest associates. Savonarola was faced with charges such as heresy, uttering prophecies, sedition, and other crimes, called religious errors by the Borgia pope. During the next few weeks all three were tortured on the rack, the torturers sparing only Savonarola’s right arm in order that he might be able to sign his confession. All three signed confessions, Savonarola doing so sometime prior to May 8. On that day he completed a written meditation on the Miserere mei, Psalm 50, entitled Infelix ego, in which he pleaded with God for mercy for his physical weakness in confessing to crimes he believed he did not commit. On the day of his execution, May 23, 1498, he was still working on another meditation, this one on Psalm 31, entitled Tristitia obsedit me.

On the day of his execution he was taken out to the Piazza della Signoria along with Fra Silvestro and Fra Domenico da Pescia. The three were ritually stripped of their clerical vestments, degraded as "heretics and schismatics", and given over to the secular authorities to be burned. The three were hanged in chains from a single cross and an enormous fire was lit beneath them. They were thereby executed in the same place where the "Bonfire of the Vanities" had been lit, and in the same manner that Savonarola had condemned other criminals himself during his own reign in Florence. Jacopo Nardi, who recorded the incident in his Istorie della città di Firenze, wrote that his executioner lit the flame exclaiming, “The one who wanted to burn me is now himself put to the flames.” Luca Landucci, who was present, wrote in his diary that the burning took several hours, and that the remains were several times broken apart and mixed with brushwood so that not the slightest piece could be later recovered, as the ecclesiastical authorities did not want Savonarola’s followers to have any relics for a future veneration of the rigorist preacher they considered a saint. The ashes of the three were afterwards thrown in the Arno beside the Ponte Vecchio.

Niccolò Machiavelli, author of The Prince, also witnessed and wrote about the execution. Subsequently, Florence was governed along more traditional republican lines, until the return of the Medici in 1512.

Savonarola's religious actions have been compared to those of the later 17th and 18th century Jansenists, although theologically many differences exist. Savonarola did not produce a theological doctrine on salvation, and faithfully adhered to even minor theological definitions of the papal Magisterium. However, Savonarola's call to simplicity in church interior and his rigorous moral stances have been compared to those of Jansenists. Also the insistence on the immediate danger of Hell and the fewness of the elect can be considered to be a similarity. After Savonarola's death, a secret Catholic group known as the Piagnoni sprang up in Florence to preserve his memory, organized into a sort of Catholic guild. Franciscan friars were prominent among the Piagnoni, and they briefly re-appeared in 1527 when they once again overthrew the Medici, but through intervention of the Holy Roman Empire of the German Nation it was brought to an end in 1530 at the Battle of Gavinana and the Medici were restored to power.

Savonarola left many admirers throughout Europe, in particular among religiously pious humanists who valued his deep spiritual convictions. Erasmus, who refused to become a Protestant, is said to have remained Catholic due to reading Savonarola. At the same time, he is considered by Protestants to be a forerunner of the Reformation because of his criticisms of the papacy.

In the twentieth century, a movement for the canonization of Frà Savonarola began to develop within the Roman Catholic Church, particularly among Dominicans, with many judging his excommunication and execution to have been unjust. His potential beatification and canonization is opposed by many Jesuits, who consider Savonarola's (secular) conflict with the papacy to have been an intolerable crime.