His literary career began with the publication of the "Dialoghi" ("Dialogues") at Venice (1542). Very famous and influential was his polemic with Giovan Battista Giraldi about the principles of theatre, involving Giraldi's tragedy "Orbecche" as well as Speroni's tragedy "Canace". Between 1560 and 1564 he lived in Rome, where he became a close friend of Annibal Caro and frequented the meetings of the "Accademia delle Notti Vaticane". He then returned to Padua, where he continued his literary production. When Ugo Boncompagni was made Pope Gregory XIII in 1572, Speroni returned to Rome. In 1578, he went back to Padua where he died on June 2, 1588.