Bernardino was born in 1380 to the noble Albizeschi family in Massa Marittima (Tuscany), a Sienese town of which his father, Albertollo degli Albizeschi, was then governor. Left orphaned at six, he was raised by a pious aunt. In 1397, after a course of civil and canon law, he joined the Confraternity of Our Lady attached to the hospital of Santa Maria della Scala church. Three years later, when the plague visited Siena, he ministered to the plague-stricken, and, assisted by ten companions, took upon himself for four months entire charge of this hospital. He escaped the plague but was so exhausted that a fever confined him for several months. In 1403 he joined the Observant branch of the Order of Friars Minor (the Franciscan Order), with a strict observance of St. Francis' Rule. Bernardino was ordained a priest in 1404 and was commissioned as a preacher the next year. About 1406 St. Vincent Ferrer, a Dominican friar and missionary, while preaching at Alessandria in the Piedmont region of Italy, allegedly foretold that his mantle should descend upon one who was then listening to him, and said that he would return to France and Spain, leaving to Bernardino the task of evangelizing the remaining peoples of Italy.
Before Bernardino, most preachers either read a prepared speech or recited a rhetorical oration. Instead of remaining cloistered and preaching only during the liturgy, Bernardino preached directly to the public. For more than 30 years, he preached all over Italy and played a great part in the religious revival of the early fifteenth century. Although he had a weak and hoarse voice, he is said to have been one of the greatest preachers of his time. His style was simple, familiar, and abounding in imagery. Cynthia Polecritti, in her biography of Bernardino, notes that the texts of his sermons “are acknowledged masterpieces of colloquial Italian.” He was an elegant and captivating preacher, and his use of popular imagery and creative language drew large crowds to hear his reflections.
Unlike many of his contemporaries, Bernardino chose his themes not from the daily liturgy, but from the ordinary lives of the people of Siena. He selected biblical themes to focus on the immediate interests of his audience. This proved effective in drawing their attention. Polecritti notes, the subject matter of his sermons reveals much about the contemporary context of 15th-century Italy.
He travelled from place to place, remaining nowhere more than a few weeks. These journeys were all made on foot. In the towns, the crowds assembled to hear him were at times so great that it became necessary to erect a pulpit on the market-place. Like Vincent Ferrer, he usually preached at dawn. His hearers, so as to ensure themselves standing room, would arrive beforehand, many coming from far-distant villages. The sermons often lasted three or four hours. He was invited to Ferrara in 1424, where he preached against the excess of luxury and immodest apparel. In Bologna, he spoke out against gambling, much to the dissatisfaction of the card manufacturers and sellers. Returning to Siena in April 1425, he preached there for 50 consecutive days. His success was claimed to be remarkable. "Bonfires of the Vanities" were held at his sermon sites, where people threw mirrors, high-heeled shoes, perfumes, locks of false hair, cards, dice, chessmen, and other frivolities to be burned. Bernardino enjoined his listeners to abstain from blasphemy, indecent conversation, and games of hazard, and to observe feast days.