He moved to Paris, where he worked as a free composer and befriended composer Rodolphe Kreutzer. The pair worked together on several operas, including ''Le petit page ou La prison d'état'' (1800) and ''Flaminius à Corinthe'' (1801). Isouard adopted the pseudonymNicolò (or Nicolò de Malte) and found rapid success in the field of opéra comique with ''Michel-Ange ''(1802) and ''L'intrigue aux fenêtres'' (1805). He composed regularly for the ''Théâtre de l'Opéra-Comique'', writing some thirty works for them.
Isouard had two daughters, Sophie-Nicole (1809–?), a composer of romances, and Annette-Julie (1814–1876), a pianist and composer. His brother Joseph (1794–1863) had a career as a singer and opera director before being named inspector of historic monuments in Rouen. Nicolas Isouard was buried in Notre-Dame-des-Victoires. A bust of the composer was placed on one of the facades of both the ''Théâtre de l'Opéra-Comique'' and the ''Palais Garnier'', and one of the main squares in Paris was given his name.