In 1641, Pope Urban elevated Cesi to Cardinal and made him Cardinal-Priest of San Marcello al Corso the following year.[2] The Pope then appointed him Legate to Perugia in 1643 and granted him a dispensation to accept an appointment as canon of the cathedral chapter of Toledo; a role that had been created by the King of Spain. When Urban died, Cesi participated in the Papal conclave of 1644, which elected Pope Innocent X. In 1645, Cesi was appointed Crown Cardinal of Sicily and held the position until 1656.