Born in Cosenza in 1509, he completed his first studies in Milan under the guidance of his uncle Antonio Telesio, a poet and man of letters who taught there, and followed him first to Rome, where he was held prisoner by the German mercenary soldiers who had captured him during the sack of 1527, then toward Venice, sojourning at Padua to study philosophy, mathematics, optics and medicine at the University's Liberal Arts Faculty. He remained there for ten years and after spending a period of meditation among the Benedictine monks, returned to his native land, where he married Diana Sersale, who gave him four children.

Afterwards he went to Naples and began work on his De rerum natura iuxta propria principia, which after two initial editions of just the first two books (Rome, 1565 and Naples, 1570), was published again in Naples in 1586 in a complete and definitive edition of nine books.

About this work, whose title was already polemical, and whose intentions were radically anti-Aristotelian and strongly critical of those who, inspecting nature, failed to take note of its processes but made themselves the measure of the rules of the universe, he was addressing it to Vincenzo Maggi of Brescia (1498-1564), one of the most renowned peripatetic philosophers of the time, who did not close the door to its principles "and could distinguish nothing that did not derive from them". In effect, while he started out with the idea of a nature that always behaved the same and was observable only through the senses, Telesio, when he was investigating the essence of heat and cold, the two main principles which instilled life into otherwise inert matter and became integral with it, did not succeed, as Francesco Patrizi (1529-1597) pointed out, in freeing physics from metaphysics, and his research, by remaining midway between philosophy and science, conflicted not so much with Aristotle as with the tendency, tinged with Platonism, to consider separate from natural phenomena, and not intrinsic to them, the very causes which they ought to explain. These limitations were quite clear to Galileo, who glided over telesianism, denying it had anything in common with his method and classifying it among the many "fantasies" of philosophers.

Despite Telesio's good relationships with various personalities who had risen to popehood (Pius IV actually wanted to make him archbishop of Cosenza, but he passed the job on to his brother) and his a priori repudiation at the end of the preface to De rerum natura of 1586 of any part of the book that might offend holy scripture, the Inquisition was not prevented from placing it, together with his pamphlets De somno and Quod animal universum, on the Index in 1596, eight years after his death, which took place shortly after his return to Cosenza. Apart from the three editions of the De rerum natura, he left a collection of minor writings, some of which were published in his lifetime, but all republished together by his pupil Antonio Persio in the posthumous Varii de naturalibus rebus libelli (Venice, 1590).