He specialized in the life and works of Claude Debussy, but also wrote numerous bibliographies, studies in the sociology of music, and historical French topics.

He succeeded Solange Corbin to the chair of musicology at the École pratique des Hautes Études in 1973.

François Lesure organized major exhibitions at the Bibliothèque nationale and the Opéra de Paris (Mozart in 1956, Debussy in 1962, Berlioz in 1969, Deux siècles d'opéra français in 1972) and at the Villa Médicis in Rome (Debussy et le symbolisme in 1984).

[2] Between 1953 and 1967 he worked at the Central Secretariat of the RISM, a global project for the identification of musical sources.

A volume of Festschriften was offered to him in 1988 upon his departure from the Bibliothèque Nationale, entitled Musiques, signes, images, which gathered contributions both international and from researchers or artists in various fields.