He began his studies in 1778 at the "School of Drawing", then attended classes at the "Society of Arts" where he studied with Jean-Étienne Liotard, among others.
A trip to Italy from 1787 to 1788 had a lasting effect on his style. He had his first showing in 1789 at the Salon of Geneva, where he presented an Étude d'après nature (Study from Nature). In 1794, he was invited to Lausanne to work for Madame de Staël.
From 1807 to 1813, he travelled throughout France, making contacts with fellow artists. From 1828 to 1829, he toured England and Scotland, receiving many commissions along the way and becoming enamored of the English "conversation pieces". He also favored a style known as "jusqu'aux genoux" (as far as the knees).
After 1820, he eschewed detailed backgrounds in favor of simple tones that emphasized the face. Until then, however, many of his portraits were done in collaboration with the landscape painter Wolfgang-Adam Töpffer and the animal painter Jacques-Laurent Agasse. Created mostly for wealthy patrons, Massot would paint the figures while his associates would fill in the backgrounds with various props that symbolized the sitter.
Perhaps because of this, very few of his paintings are signed and attribution is often difficult. It is believed that approximately 250 works are authentically his. Many prominent women were among his sitters, including Madame Recamier, the Empress Josephine and Queen Hortense.
In 1799, he was named Director of the "Écoles de dessin de la ville de Genève" and, the following year, became a member of the art society.