Gerard was an older brother of Cornelis van Spaendonck (1756-1840), who was also a well-known painter. In the years 1760-1769 he studied in Antwerp with the decorative painter Willem Herreyns. In 1769 he moved to Paris, and in 1774, through the mediation of Claude-Henri Watelet, at the age of 28, he was appointed miniature painter at the court of Louis XVI. He exhibited for the first time in 1777. In 1780 he succeeded Françoise Basseporte (1701-1780) as professor of flower painting at the Jardin des Plantes. Shortly afterwards he was elected a member of the Académie des beaux-arts.

Van Spaendonck painted in both oil and watercolor. He made more than fifty works for the Vélins du Roi, a renowned collection of botanical watercolors owned by the French royal family. From 1799 to 1801 he published 24 plates of his Fleurs Dessinées d'après Nature (Flowers drawn from life); high quality engravings for flower painting students. Today Fleurs dessinées d'après nature is a highly regarded book in the field of flower painting.

In 1788 Van Spaendonck was appointed advisor to the Académie, and in 1795 he was one of the founders of the Institut de France. In 1804 he was awarded the Legion of Honour. Shortly afterwards he was ennobled by Napoleon Bonaparte. Van Spaendonck died in 1822 at the age of 76.

At Groeseindstraat 99 in Tilburg, a plaque can be seen where the birthplace of the Van Spaendonck brothers used to be. Besides painter Karel Appel, Gerard van Spaendonck is the only Dutchman to be buried at Père Lachaise in Paris. Gerard is right behind Chopin's grave.