Biglio was nominated for the papacy during the conclave of 1878 but received only a handful of votes. The conclave elected Gioachino Pecci, who took the papal throne as Pope Leo XIII. Biglio was soon appointed as Prefect of the Sacred Congregation of Indulgences and Relics by Pope Leo in 1878. Pope Leo also appointed him to serve as Apostolic Penitentiary on 18 October 1877, a position he held until his death. He also served as Secretary of the Holy Office from January 1883 until his death one year later.