Gerard was an older brother of Cornelis van Spaendonck (1756-1840), who was also a renowned artist. In the 1760s he studied with decorative painter Guillaume-Jacques Herreyns (1743-1827) in Antwerp. In 1769 he moved to Paris, and in 1774 was appointed miniature painter in the court of Louis XVI. In 1780 he succeeded Madeleine Françoise Basseporte (1701-1780) as professor of floral painting at the Jardin des Plantes, and shortly afterwards was elected a member of the Académie des beaux-arts.
Gerard van Spaendonck painted with both oil and watercolors. He contributed over fifty works to the Vélins du Roi, which was a famous collection of botanical watercolors possessed by French royalty. From 1799 to 1801 he published twenty-four plates of his Fleurs Dessinees d'apres Nature (Flowers Drawn from Life), which were high-quality engravings for students of floral painting. Today, Fleurs Dessinees d'apres Nature is a highly treasured book on floral art.
In 1788 Spaendonck was appointed adviser to the Académie, and in 1795 he became a founding member of the Institut de France. In 1804 he received the Légion d'honneur and soon afterwards was ennobled by Napoleon Bonaparte.
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