Third marriage: Alfonso I d'Este (Duke of Ferrara)
Lucrezia married Alfonso I d'Este by proxy in Rome on 30 December 1501, with his brother Ferrante d'Este standing in for the groom, then in person on 2 February 1502 in Ferrara. Lucrezia's progress from Rome to Ferrara was through the Apennine Mountains and she both rode on horseback and was carried in a sedan chair, and was accompanied by ladies, retainers, musicians, and her brother Cesare.
Despite having given birth to a child, Lucrezia was obliged to simulate the appearance of a virgin spouse in order to marry d'Este and was forced to leave Rodrigo of Aragon, her only child by Alfonso of Aragon, behind. Lucrezia tried many times to have little Rodrigo in Ferrara, but her plans were ruined. She sent him gifts and letters and, when he was 9 years old, an educator from the University of Ferrara.
Lucrezia became Duchess of Ferrara from 1505 after the death of Alfonso's father Ercole. She gave birth to six children during her marriage to d'Este, including the future Duke of Ferrara, Ercole II d'Este.However, neither partner was faithful. Beginning in 1503, Lucrezia enjoyed a long relationship with her brother-in-law, Francesco II Gonzaga, Marquis of Mantua. Francesco's wife was the cultured intellectual Isabella d'Este, the sister of Alfonso, to whom Lucrezia had made overtures of friendship, to no avail. The affair between Francesco and Lucrezia was passionate, more sexual than sentimental, as can be attested in the fevered love letters the pair wrote one another. It has been claimed that the affair ended when Francesco contracted syphilis and had to end sexual relations with Lucrezia. This may not be true, however, as Francesco had contracted syphilis before 1500; it was known that he passed the disease onto his eldest son, Federico Gonzaga, who was born in 1500. Francesco did not meet Lucrezia until 1502.
Lucrezia also had a love affair with the poet Pietro Bembo during her third marriage. Their love letters were deemed "the prettiest love letters in the world" by the Romantic poet Lord Byron when he saw them in the Ambrosian Library of Milan on 15 October 1816. The letters were published in 1859 under the title Lettere di Lucrezia Borgia a messer Pietro Bembo.
Due to Lucrezia's influence as a patron of the arts, the court of d'Este became a centre for aspiring Renaissance writers, musicians, poets and philosophers, including Ludovico Ariosto and Gian Giorgio Trissino. She was considered a respectable and accomplished Renaissance duchess, effectively rising above her previous reputation and surviving the fall of the Borgias following her father's death in 1503. She played a diplomatic role at the Ferrarese court, meeting with envoys and ruling the territory as regent twice during Alfonso's absences on military campaigns. She is also known to have overseen the management of her finances, buying and selling properties, buying marshland at a low cost then investing in reclamation enterprises, and renting parts of her newly arable land for short terms, which contributed to a nearly doubling of her annual income. She was a patron of charities and ecclesiastical foundations.
Lucrezia was devastated upon Cesare's death in 1507. In 1510, Lucrezia's husband was excommunicated and Ferrara was placed under interdict by Pope Julius II. In response, she pawned her jewels to pay for the city's defense and entertained French troops that had come to Ferrara's aid. She met the famed French soldier, the Chevalier Bayard, while the latter was co-commanding the French allied garrison of Ferrara. According to his biographer, the Chevalier became a great admirer of Lucrezia's, considering her a "pearl on this Earth".
After a long history of complicated pregnancies and miscarriages, on 14 June 1519, Lucrezia gave birth to her tenth child, which she named Isabella Maria, in honour of Alfonso's sister, Isabella d'Este. Fearing the sickly child would die unbaptised, Alfonso ordered her to be baptized immediately, and Isabella died the same day. Eleonora Pico della Mirandola and Count Alexandro Serafino were chosen as godparents.
Lucrezia had become very weak during the pregnancy, and fell seriously ill after the birth. After seeming to recover for two days, she worsened again, and died on 24 June 1519 at Belriguardo Castle, aged 39. Her body was shrouded in the habit of a tertiary Franciscan and she was buried in the convent of Corpus Domini in Ferrara, Emilia-Romagna, where she had requested to be interred. She was deeply mourned by the people of Ferrara.
After Lucrezia's death, her brother-in-law Giovanni Gonzaga wrote to Isabella d'Este that: "It is said that the Duchess left behind a good amount of money, but the exact amount is unknown."
