Born in Briançon, the son and grandson of physicians, he was educated in Paris (Collège de Navarre), and obtained a degree in medicine in 1522. He was imprisoned in 1524, probably for practicing judicial astrology.

In 1531, he was appointed to the chair of mathematics at the Collège Royal (the present Collège de France), founded by Francis I of France, where he taught until his death.

Although primarily a populariser, Fine was one of the most prolific authors of mathematical books of his age. He worked in a wide range of mathematical fields, including practical geometry, arithmetic, optics, gnomonics, astronomy, and instrumentalism.

He gave the value of pi to be (22 2/9)/7 in 1544. Later, he gave 47/15 and, in De rebus mathematicis (1556), he gave 3 11/78.

In 1542 Fine published De mundi sphaera (On the Heavenly Spheres), a popular astronomy textbook with woodcut illustrations. His writing on astronomy included guides to the use of astronomical equipment and methods (e.g. the ancient practice of determining longitude through the coordinated observation of lunar eclipses from two fixed points with enough distance between them to make the phenomena appear at different times of the night.) He also described more recent innovations, such as an instrument he called a méthéoroscope (an astrolabe modified by adding a compass).

Explanatory work was complemented by direct contributions. His woodcut map of France (1525) is one of the first of its kind. He constructed an ivory sundial in 1524, which still exists.

Fine's heart shaped (cordiform) map projection may be his most famous illustration, and was frequently employed by other notable cartographers, including Peter Apian and Gerardus Mercator.

Fine attempted to reconcile discoveries in the New World with old medieval legends and information (derived from Ptolemy) regarding the Orient. Thus, on one of his two world maps, Nova Universi Orbis Descriptio (1531), the legend marked Asia covers both North America and Asia, which were represented as one landmass. He used the toponym "America" for South America, and thus Marco Polo's Mangi, Tangut, and Catay appear on the shores of the present day Gulf of Mexico. On the same map, Fine drew Terra Australis to the south, including the legend "recently discovered but not yet completely explored," by which Finé meant the discovery of Tierra del Fuego by Ferdinand Magellan.

Fine’s cosmography was derived from the German mathematician and cosmographer, Johann Schoener. In his study of Schöner‘s globes, Franz von Wieser, found that the derivation of Fine’s mappemonde from them was “unmistakeable (unverkennbar)”. Lucien Gallois also noted the undeniable “ressemblance parfaite” between Fine’s 1531 mappemonde and Schoener’s globe of 1533. As Schoener’s globe of 1523, which also closely resembled Fine’s mappemonde, was not identified until 1925 by Frederik (F.C.) Wieder, Gallois was forced to argue that Fine, who said he had been working on his mappemonde since 1521, had had direct or indirect personal communication with Schoener or had drawn upon his 1515 Luculentissima descriptio. Wieder’s identification of Schoener’s map gores of 1523 strengthens Gallois’ case for Fine’s reliance upon Schoener.

Fine died in Paris at age 60. The lunar crater Orontius named after him, uses his Latinized name.

Jean Clouet is said to have painted a portrait of Fine in 1530, when Fine was 36. With the original painting lost, the rendering is now known only through prints derived from the original image.