Ariosto was born in Reggio Emilia, where his father Niccolò Ariosto was commander of the citadel. He was the oldest of ten children and was seen as the successor to the patriarchal position of his family. From his earliest years, Ludovico was very interested in poetry, but he was obliged by his father to study law. After five years of law, Ariosto was allowed to read classics under Gregorio da Spoleto. Ariosto's studies of Greek and Latin literature were cut short by Spoleto's move to France to tutor Francesco Sforza. Shortly after, Ariosto's father died.

After the death of Ariosto's father, Ludovico was compelled to forgo his literary occupations and take care of his family, whose affairs were in disarray. Despite his family obligations, Ariosto managed to write some comedies in prose as well as lyrical pieces. Some of these attracted the notice of Cardinal Ippolito d'Este, who took the young poet under his patronage and appointed him one of the gentlemen of his household. Este compensated Ariosto poorly for his efforts. The only reward he gave the poet for Orlando Furioso, a piece dedicated to him, was the question, "Where did you find so many stories, Master Ludovic?" The poet himself tells us that the cardinal was ungrateful, that he deplored the time which he spent under his yoke, and adds, that if he received some niggardly pension, it was not to reward him for his poetry, which the prelate despised, but to make some just compensation for the poet's running like a messenger, with the work of his life yet to accomplish, at his eminence's pleasure. Nor was even this miserable pittance regularly paid during the period that the poet enjoyed it.

The cardinal went to Hungary in 1518, and wished Ariosto to accompany him. The poet excused himself, pleading ill health, his love of study, the care of his private affairs and the age of his mother, whom it would have been disgraceful to leave. His excuses were not well received, and even an interview was denied him. Ariosto then boldly said, that had his eminence thought to have bought a slave by assigning him the scanty pension of seventy-five crowns a year, he was mistaken and might withdraw his boon — which it seems the cardinal did.

The cardinal's brother, Alfonso, duke of Ferrara, now took the poet under his patronage. This was but an act of simple justice, Ariosto having already distinguished himself as a diplomat, chiefly on the occasion of two visits to Rome as ambassador to Pope Julius II. The fatigue of one of these hurried journeys brought on a complaint from which he never recovered, and on his second mission he was nearly killed by order of the pope, who happened at the time to be much incensed against the duke of Ferrara.

On account of the war, his salary of only 84 crowns a year was suspended, and it was withdrawn altogether after the peace. Because of this, Ariosto asked the duke either to provide for him, or to allow him to seek employment elsewhere. He was appointed to the province of Garfagnana, then without a governor, situated on the wildest heights of the Apennines, an appointment he held for three years. The place was no sinecure. The province was distracted by factions and banditi, the governor had not the requisite means to enforce his authority and the duke did little to support his minister. Yet it is said that Ariosto's government satisfied both the sovereign and the people given over to his care; indeed, there is a story about a time when he was walking alone and fell into the company of a group of banditi, the chief of which, on discovering that his captive was the author of Orlando Furioso, humbly apologized for not having immediately shown him the respect which was due to his rank.

In 1508 his play Cassaria appeared, and the next year I Suppositi. In 1516, the first version of the Orlando Furioso in forty cantos, was published at Ferrara. The third and final version of the Orlando Furioso, in forty-six cantos, appeared on September 8, 1532. Throughout Ariosto's writing are narratorial comments dubbed by Dr. Daniel Javich as "Cantus Interruptus". These sections are short breaks in the text in which the narrator destroys the fourth wall and talks directly to the audience. Whether this is for comedic reasons or is just a continuation of the oral tradition, Ariosto uses it throughout his works. For example, in Canto II, stanza 30, of Orlando Furioso, the narrator says:

But I, who still pursue a varying tale,

Must leave awhile the Paladin, who wages

A weary warfare with the wind and flood;

To follow a fair virgin of his blood.

Some have attributed this piece of metafiction as one component of the "Sorriso ariostesco" or Ariosto smile, the wry sense of humor that Ariosto adds to the text. In explaining this humor, Thomas Greene, in his critical work Descent from Heaven, says "the two persistent qualities of Ariosto's language are first, serenity - the evenness and self-contented assurance with which it urbanely flows, and second, brilliance - the Mediterranean glitter and sheen which neither dazzle nor obscure but confer on every object its precise outline and glinting surface. Only occasionally can Ariosto's language truly be said to be witty, but its lightness and agility create a surface which conveys a witty effect. Too much wit could destroy even the finest poem, but Ariosto's graceful brio is at least as difficult and for narrative purposes more satisfying".