Niccolò Caetani was born in Rome on February 23, 1526, the son of Camillo Caetani, 3rd duke of Sermoneta, a cousin of Pope Paul III, and his second wife, Flaminia Savelli. His families were patricians from Naples. He was the uncle of Cardinal Enrico Caetani.
At the age of 10, Pope Paul III made him a cardinal deacon in pectore in the consistory of December 22, 1536. On March 5, 1537, he became administrator of the Diocese of Bisignano. His elevation to the cardinalate was published in the consistory of March 13, 1538; he received the red hat and the deaconry of San Nicola in Carcere on April 16, 1538.
He participated in both the papal conclave of April 1555 that elected Pope Marcellus II and the papal conclave of May 1555 that elected Pope Paul IV. He later participated in the papal conclave of 1559 that elected Pope Pius IV.
On January 7, 1560, he was named governor of Cesi, Terni. He resigned the administration of Quimper on April 5, 1560. He participated in the papal conclave of 1565-66 that elected Pope Pius V. In 1570, he became cardinal protector of the Kingdom of Scotland. He participated in the papal conclave of 1572 that elected Pope Gregory XIII.
He participated in the papal conclave of 1585 that elected Pope Sixtus V. He died on the day of the papal coronation, May 1, 1585. His body was transferred to Loreto and he is buried there in the Basilica della Santa Casa.