Around the year 1539, Montaigne was sent to study at a prestigious boarding school in Bordeaux, the Collège de Guyenne, then under the direction of the greatest Latin scholar of the era, George Buchanan, where he mastered the whole curriculum by his thirteenth year. He then began his study of law at the University of Toulouse in 1546 and entered a career in the local legal system. He was a counselor of the Court des Aides of Périgueux and, in 1557, he was appointed counselor of the Parlement in Bordeaux (a high court). From 1561 to 1563 he was courtier at the court of Charles IX; he was present with the king at the siege of Rouen (1562). He was awarded the highest honour of the French nobility, the collar of the Order of St. Michael, something to which he aspired from his youth. While serving at the Bordeaux Parlement, he became very close friends with the humanist poet Étienne de la Boétie, whose death in 1563 deeply affected Montaigne. It has been suggested by Donald M. Frame, in his introduction to The Complete Essays of Montaigne that because of Montaigne's "imperious need to communicate" after losing Étienne, he began the Essais as his "means of communication" and that "the reader takes the place of the dead friend".

Montaigne married Françoise de la Cassaigne in 1565, probably in an arranged marriage. She was the well-got daughter and niece of merchants of Toulouse and Bordeaux. They had six daughters, but only the second-born, Léonor, survived infancy. Little is known about their marriage, a few words only escaping from Montaigne himself on the subject – he wrote of his daughter Léonor, "All my children die at nurse; but Léonore, our only daughter, who has escaped this misfortune, has reached the age of six and more without having been punished, the indulgence of her mother aiding, except in words, and those very gentle ones." His daughter married François de la Tour and later Charles de Gamaches and had a daughter by each.

Following the petition of his father, Montaigne started to work on the first translation of the Catalan monk Raymond Sebond's Theologia naturalis, which he published a year after his father's death in 1568 (In 1595, Sebond's Prologue was put on the Index Librorum Prohibitorum for its declaration that the Bible is not the only source of revealed truth). After this, he inherited the family's estate, the Château de Montaigne, to which he moved back in 1570, thus becoming the Lord of Montaigne. Another literary accomplishment was Montaigne's posthumous edition of his friend Boétie's works.

In 1571, he retired from public life to the Tower of the Château, his so-called "citadel", in the Dordogne, where he almost totally isolated himself from every social and family affair. Locked up in his library, which contained a collection of some 1,500 works, he began work on his Essais ("Essays"), first published in 1580. On the day of his 38th birthday, as he entered this almost ten-year period of self-imposed reclusion, he had the following inscription crown the bookshelves of his working chamber:

In 1578, Montaigne, whose health had always been excellent, started suffering from painful kidney stones, a sickness he had inherited from his father's family. Throughout this illness, he would have nothing to do with doctors or drugs. From 1580 to 1581, Montaigne traveled in France, Germany, Austria, Switzerland, and Italy, partly in search of a cure, establishing himself at Bagni di Lucca where he took the waters. His journey was also a pilgrimage to the Holy House of Loreto, to which he presented a silver relief depicting himself and his wife and daughter kneeling before the Madonna, considering himself fortunate that it should be hung on a wall within the shrine. He kept a fascinating journal recording regional differences and customs and a variety of personal episodes, including the dimensions of the stones he succeeded in ejecting from his bladder. This was published much later, in 1774, after its discovery in a trunk which is displayed in his tower.

His fame rests on the Essais, a collection of a large number of short subjective treatments of various topics published in 1580, inspired by his studies in the classics, especially by the works of Plutarch and Lucretius. Montaigne's stated goal is to describe humans, and especially himself, with utter frankness. Montaigne's writings are studied as literature and philosophy around the world.

While in the city of Lucca in 1581, he learned that, like his father before him, he had been elected mayor of Bordeaux; he returned and served as mayor. He was re-elected in 1583 and served until 1585, again moderating between Catholics and Protestants. The plague broke out in Bordeaux toward the end of his second term in office, in 1585. In 1586, the plague and the Wars of Religion prompted him to leave his château for two years.

Montaigne continued to extend, revise, and oversee the publication of Essais. In 1588 he wrote its third book and also met the Writer Marie de Gournay, who admired his work and later edited and published it. Montaigne called her his adopted daughter. King Henry III was assassinated in 1589, and Montaigne then helped to keep Bordeaux loyal to Henry of Navarre, who would go on to become King Henry IV.

Montaigne died of quinsy at the age of 59, in 1592 at the Château de Montaigne. The disease in his case "brought about paralysis of the tongue", and he had once said "the most fruitful and natural play of the mind is conversation. I find it sweeter than any other action in life; and if I were forced to choose, I think I would rather lose my sight than my hearing and voice." Remaining in possession of all his other faculties, he requested mass, and died during the celebration of that mass.

The Essais exercised important influence on both French and English literature, in thought and style. Francis Bacon's Essays, published over a decade later, in 1596, are usually assumed to be directly influenced by Montaigne's collection, and Montaigne is cited by Bacon alongside other classical sources in later essays.

Ever since Edward Capell first made the suggestion in 1780, scholars have suggested Montaigne to be an influence on Shakespeare. The latter would have had access to John Florio's translation of Montaigne's Essais, published in English in 1603, and a scene in The Tempest "follows the wording of Florio [translating Of Cannibals] so closely that his indebtedness is unmistakable". However, most parallels between the two can be explained as commonplaces: as with Cervantes, Shakespeare's similarities with Writers in other nations could be due simply to their simultaneous study of Latin moral and philosophical Writers such as Seneca the Younger, Horace, Ovid and Virgil.

The American Philosopher Eric Hoffer employed Montaigne both stylistically and in thought. In Hoffer's memoir, Truth Imagined, he said of Montaigne, "He was writing about me. He knew my innermost thoughts." The Welsh Novelist John Cowper Powys expressed his admiration for Montaigne's philosophy in his books Suspended Judgements (1916) and The Pleasures of Literature (1938). Judith N. Shklar introduces her book Ordinary Vices (1984), "It is only if we step outside the divinely ruled moral universe that we can really put our minds to the Common ills we inflict upon one another each day. That is what Montaigne did and that is why he is the hero of this book. In spirit he is on every one of its pages..."

Montaigne’s views on child education continue to have an influence in the present. Variations of Montaigne’s ideas on education are incorporated into modern learning in some ways. He argued against the popular way of teaching in his day, encouraging individualized learning. He believed in the importance of experience over book learning and memorization. Ultimately, Montaigne postulated that the point of education was to teach a student how to have a successful life by practising an active and socially interactive lifestyle.