In 1681, Pozzo was called to Rome by Giovanni Paolo Oliva, Superior General of the Jesuits. Among others, Pozzo worked for Livio Odescalchi, the powerful nephew of the pope, Innocent XI. Initially he was used as a stage designer for biblical pageants, but his illusionistic paintings in perspective for these stages soon gave him a reputation as a virtuoso in wall and ceiling decorations.
Meanwhile he continued painting frescoes and illusory domes in Turin, Mondovì, Modena, Montepulciano and Arezzo. In 1681 he was asked by Cosimo III de' Medici, Grand Duke of Tuscany to paint his self-portrait for the ducal collection (now in the Uffizi in Florence). This oil on canvas has become a most original self-portrait. It shows the painter in a diagonal pose, showing with his right index finger his illusionist easel painting (a trompe-l'œil dome, perhaps of the Badia church in Arezzo) while his left hand rests on three books (probably alluding to his not-yet published treatises on perspective). The painting was sent to the duke in 1688. He also painted scenes from the life of St Stanislaus Kostka in the saint's rooms of the Jesuit novitiate of Sant'Andrea al Quirinale in Rome.