She taught at several institutions in the United States, including Wellesley College in Massachusetts and as Henri Focillon Professor of Art and Archaeology at Harvard University.

[2] The two theses (graduates students then had to submit two theses) that she presented for her doctorat d'etat, "L'illustration du roman de Barlaam et Joasaph" and a paper on Armenian illuminated manuscripts during the late medieval period,[4] were well-received (earning a Mention très honorable), and both were awarded with prizes by the Académie des Inscriptions et Belles-Lettres and Revue des Études Grecques when they were published in 1937.

In 1930, Der Nersessian moved to the United States at the suggestion of her three mentors, Byzantinists Charles Rufus Morey, Albert M. Friend Jr., and Walter Cook, becoming a part-time lecturer at Wellesley College in Massachusetts.

Shortly after her death in 1989, an endowment fund for prospective art history students in Armenia, the Fonds Sirarpie Der Neressian at the Institut de Recherches sur les Miniatures Arméno-Byzantines, was created in her honor.

[4] Der Nersessian's scholarly output chiefly focused on art history, and more specifically on the study of church architecture, illuminated manuscripts, miniatures and sculpture.