A member of the Orsini family, Franciotto Orsini was born in Rome in 1473, the son of Orso Orsini di Monteredondo and Costanza Savelli. He was a nephew of Pope Leo X on his father's side. Orsini was educated in Florence by Lorenzo de' Medici.
Early in his life, he participated in several military exercises, fighting against the forces of Cesare Borgia. He married Violante Orsini di Mugnano and had five legitimate children. After his wife's death, he entered the ecclesiastical estate.
He was administrator of the see of Nicastro from September 15, 1517 to May 5, 1518. He became archpriest of St. Peter's Basilica. On January 18, 1519, he was named administrator of the see of Boiano, holding this post until July 24, 1523. He was deposed from the cardinalate on August 8, 1519, though later reinstated. Sometime after 1519, he opted for the deaconry of Santa Maria in Cosmedin.