Santa Maria in Domnica
After being the abbot of Farfa in 1482, Orsini was nominated as the deacon cardinal of Pope Sixtus IV in the consistory of the 15th of November 1483, receiving the diakonia of Santa Maria in Domnica. He received the deaconry of Santa Maria in Domnica. and the red hat on November 19, 1483. Already in 1484, he had participated in the conclave that elected Pope Innocent VIII. The new pope named Cardinal Orsini papal legate to the March of Ancona on September 22, 1484. The Orsini were hostile to Pope Cybo, but Giovanni Battista proved his qualities as a peacemaker, avoiding too strong a fracture between the papacy and his family. At the end of the year, he was nominated as the papal legate from Marche, and on January 22, 1485, he obtained from the pope the permit to fortify the region to resist the continuous attacks from the Ottomans. He returned to Rome in 1486 to try to fix the disagreement between the Orsini family and the Pope. In the end of 1488, he renounced the deacon of Santa Maria in Domnica, opting instead for that of Santa Maria Nuova.