A law student at Erfurt, Heinse met the writer Christoph Martin Wieland and through him Johann Wilhelm Ludwig Gleim (Gleim, Johann Wilhelm Ludwig), who was known for his patronage of young poets and who in 1772 procured Heinse a post as tutor in a family in Quedlinburg. In 1774 he went to Düsseldorf, where he helped edit Iris, a periodical for women. After traveling in Italy between 1780 and 1783, he returned to Germany to become librarian to the Archbishop of Mainz at Aschaffenburg.

In Heinse's famous novel Ardinghello und die glückseligen Inseln (1787; “Ardinghell and the Blessed Islands”), the hero is an artist and a dreamer who founds a utopia on a Greek island. Glorifying eroticism and the aesthetic life, it is a forerunner of the Künstlerroman (“artist novel”) of the Romantic movement. His second novel, Hildegard von Hohenthal (1795–96; “Hildegard of Hohenthal”), in which music plays the role that painting had done in Ardinghello, is considered a contribution to musical criticism. In a critical work, Über einige Gemälde der Düsseldorfer Galerie (1776–77; “On Several Paintings in the Düsseldorf Gallery”), he stresses the dependence of artistic production on historical and national circumstances and expresses particular appreciation of Peter Paul Rubens.