Orsini's first wife was Francesca d'Alviano. His second wife was Maddalena Orsini, with whom he had four children:
- Rinaldo [it] (died 1509), archbishop of Florence
- Aurante (c. 1450 – post 1497), married firstly Gian Ludovico Pio, who was executed in 1469 for having participated in a plot against Duke Borso d'Este; married secondly Lorenzo Malaspina di Gragnola
- Clarice Orsini (1453–1488), married Lorenzo de' Medici
- Orso Organtino (died 1479), his successor