She is best known for her acting in silent films, and rose to public attention for roles in the Louis Feuillade serials Les Vampires as Irma Vep and in Judex as Marie Verdier.

With her heavily kohled dark eyes, somewhat sinister make-up, pale skin and exotic wardrobes, Musidora quickly became a highly popular and instantly recognizable presence of European cinema.

Though not intended to be avant-garde, Les Vampires and Judex were lauded by Louis Aragon and Andre Breton in the 1920s for the films' elements of surprise, fantasy/science fiction, unexpected juxtapositions and visual non sequiturs.

Filmmakers Fritz Lang, Luis Buñuel, Georges Franju, Alain Resnais, and Olivier Assayas have cited Les Vampires and Judex as influencing them in their desires to become directors.

Late in her life, she would occasionally work in the ticket booth of the Cinémathèque Française—few patrons realized that the older woman in the foyer might be starring in the film they were watching.