Although he was an immensely capable general and statesman, Cesare would have trouble maintaining his domain without continued Papal patronage. Niccolò Machiavelli cites Cesare's dependence on the good will of the Papacy, under the control of his father, to be the principal weakness of his rule. Machiavelli argued that, had Cesare been able to win the favor of the new Pope, he would have been a very successful ruler. The news of his father's death (1503) arrived when Cesare was planning the conquest of Tuscany. While he was convalescing in Castel Sant'Angelo, his troops controlled the conclave. The new pope, Pius III, supported Cesare Borgia and reconfirmed him as Gonfalonier; but after a brief pontificate of twenty-six days he died. Borgia's deadly enemy, Giuliano Della Rovere, then succeeded by dexterous diplomacy in tricking the weakened Cesare Borgia into supporting him by offering him money and continued papal backing for Borgia policies in the Romagna; promises which he disregarded upon election. He was elected as Pope Julius II to the papal dignity by the near-unanimous vote of the cardinals. Realizing his mistake by then, Cesare tried to correct the situation to his favor, but Pope Julius II made sure of its failure at every turn.
Cesare Borgia was betrayed while in Naples by Gonzalo Fernández de Córdoba, a man he had considered his ally, and exiled to Spain in 1504, while his lands were retaken by the Papacy. He was imprisoned first in the Castle of Chinchilla de Montearagón but after an attempted escape was moved to the Castle of La Mota, Medina del Campo. He did manage to escape from the Castle of La Mota with assistance and joined King John III of Navarre. He was killed in the early morning of March 13th, 1507 while fighting just outside of the city of Viana, Spain.

Borgia was originally buried in a marble tomb beneath the altar of the Church of Santa Maria in Viana, one of the stops on the Camino de Santiago. In the 16th century the bishop of Mondoñedo, Antonio de Guevara, published from memory what he had seen written on the tomb when he had paid a visit to the church. This epitaph underwent several changes in wording and meter throughout the years and the version most commonly cited today is that published by the priest and historian Francisco de Alesón in the 18th century. It reads:
Aquí yace en poca tierra el que todo le temía el que la paz y la guerra en su mano le tenía. Oh tú que vas a buscar dignas cosas de loar: si tú loas lo más digno, aquí pare tu camino, no cures de más andar.
Roughly translated into English it says, "Here lies in a little earth he who everyone feared, he who held peace and war in his hand. Oh, you who go in search of worthy things to praise, if you would praise the worthiest then your path stops here and you do not need to go any farther."
The tomb was destroyed sometime between 1523 and 1608, during which time Santa María was undergoing renovation and expansion and the opportunity was taken to tear down the monument and expel Borgia's bones to where they were reburied under the street in front of the church to be trodden on by all who walked through the town. Blasco Ibáñez, in A los pies de Venus, writes that the then Bishop of Santa María had Borgia expelled from the church because his own father had died after being imprisoned under Alexander VI. It was held for many years that the bones were lost, although in fact local tradition continued to mark their place quite accurately and folklore sprung up around Borgia's death and ghost. The bones were in fact dug up twice and reburied once by historians (both local and international--the first dig in 1886 involved the French historian Charles Yriarte, who also published works on the Borgias) seeking the resting place of the infamous Cesare Borgia. After Borgia was unearthed for the second time in 1945 his bones were taken for a rather lengthy forensic examination by Victoriano Juaristi, a surgeon by trade and Borgia aficionado, and the tests concurred with the preliminary ones carried out in the 19th century. There was evidence that the bones belonged to Borgia.
Cesare Borgia's remains then were sent to Viana's town hall, directly across from Santa María, where they remained until 1953. They were then reburied immediately outside of the Church of Santa María, no longer under the street and in direct danger of being stepped on. A memorial stone was placed over it which translated into English declared Borgia the Generalisimo of the papal as well as the Navarran forces. A movement was made in the late 80s to have Borgia dug up once more and put back into Santa María, but this proposal was ultimately rejected by church officials due to recent ruling against the internment of anyone who did not hold the title of pope or cardinal. Since Borgia had renounced the cardinalate it was decided that it would be inappropriate for his bones to be moved into the church.

Cesare Borgia briefly employed Leonardo da Vinci as military architect and engineer between 1502 and 1503. Cesare provided Leonardo with an unlimited pass to inspect and direct all ongoing and planned construction in his domain[citation needed]. Before meeting Cesare, Leonardo had worked at the Milanese court ofLudovico Sforza for many years, until Louis XII of France drove Sforza out of Italy. After Cesare, Leonardo was unsuccessful in finding another patron in Italy. King Francis I of France was able to convince Leonardo to enter his service, and the last three years of da Vinci's life were spent working in France.