Cesare was born on 13 September 1475. He was the son of Pope Alexander VI (r. 1492–1503) and his long-term mistress Vannozza dei Cattanei. He was the brother of Lucrezia Borgia; Giovanni Borgia (Juan), Duke of Gandia; and Gioffre Borgia (Jofré in Catalan), Prince of Squillace.

After initially entering the church and becoming a cardinal on his father's election to the Papacy, he became the first person to resign a cardinalcy after the death of his brother in 1498. His father set him up as a prince with territory carved from the Papal States, but after his father's death he was unable to retain power for long, according to Machiavelli this was due to his planning for all possibilities but his own illness. After escaping from prison Cesare died fighting in Spain.

On 10 May 1499, Cesare married Charlotte of Albret (1480 – 11 March 1514). She was a sister of John III of Navarre. They were parents to a daughter, Louise Borgia, Duchess of Valentinois, (1500–1553) who first married Louis II de la Trémoille, Governor of Burgundy, and secondly Philippe de Bourbon (1499–1557), Seigneur de Busset.

Cesare was also father to at least 11 illegitimate children, among them Girolamo Borgia, who married Isabella Contessa di Carpi, and Lucrezia Borgia (the younger), who, after Cesare's death, was moved to Ferrara to the court of her aunt, the elder Lucrezia Borgia.