The main characters in Walter Isaacson's book "Leonardo da Vinci" include notable figures from the Renaissance period, each contributing to Leonardo's life and legacy. Cesare Borgia, the illegitimate son of Pope Alexander VI, is depicted as a warrior and a significant influence on Machiavelli's work. He was also a patron to Leonardo, highlighting the connection between politics and art during that era. Another key character is Donato Bramante, a renowned architect and friend of Leonardo, who played a crucial role in several architectural masterpieces including St. Peter's Basilica.

Additionally, the book introduces Caterina Lippi, an orphan and Leonardo's mother, who offers insight into the artist's early life and family background. Caterina's journey from a humble beginning to raising a remarkable son adds depth to Leonardo's personal history. Lastly, Charles d'Amboise, who served as the French governor of Milan and patronized Leonardo, underscores the importance of patrons in the success of artists during the Renaissance. Collectively, these figures paint a vivid picture of the time in which Leonardo lived and thrived.