The following version of the book was used to create this study guide: Isaacson, Walter. Leonardo Da Vinci. Simon and Schuster, 2017. First Hardcover Edition.

After opening with a thematic introduction to the person of Leonardo Da Vinci, Isaacson begins his biography from the artist's childhood. Being born out of wedlock freed Leonardo from continuing the family legacy as a notary and he was apprenticed to a successful Florentine painter named Verrocchio instead. Isaacson explores how Verrochio's studio may have influenced the development of Leonardo's early style as a painter, both through collaborative and solo projects. After striking out on his own, Leonardo established a strong reputation as a painter in Florence but left several works unfinished. About to turn thirty, the young painter decided to leave Florence to seek new patronage from the duke in Milan.

Although Leonardo was keen to work for the Milanese duke as a military engineer instead of as a painter, much of his early work in Milan was as a court entertainer. Isaacson argues that many of his early inventions were intended for theatrical use. In Milan, Leonardo also began a relationship with a young man known as Salai who was both student and companion. It is also likely that Leonardo's relationship with Salai eventually became romantic and/or sexual as well. Working on various collaborations with other great minds of the era furthered Leonardo's interest in proportion and geometry, which culminated most famously in his drawing of the Vitruvian Man. While in Milan, Leonardo worked on several projects for the duke including portraits of ducal mistresses and a large-scale horse sculpture which was never completed due to outside political tensions. Leonardo also pursued his own curiosities through the copious amounts of observation and experimentation that he is known for. Among other things, he studied the flight of birds, developed and designed machinery, experimented with geometric problems, and studied human anatomy. Leonardo's varied interests and pursuits reinforced a strong connection between the arts and sciences throughout his life and work. Arguably, Leonardo's most significant project during this period in Milan is the painting of The Last Supper which Isaacson considers both an example of and metaphor for Leonardo's genius.

Turmoil in Leonardo's personal and professional life, as well as political strife between Milan and France prompted Leonardo to return to Florence in 1500. Now approaching fifty, Leonardo embraced his distinctive character and rejected appeals from wealthy patrons such as Isabella d'Este whose proposed projects held no appeal for him. Instead he worked on several other paintings including Mona Lisa, Virgin and Child with Saint Anne, and "and image of Leda and the swan that is now lost" (300). He also continued his studies in mathematics and anatomy. In the early 1500s, Leonardo was able to pursue his ambitions as a military engineer more directly through the patronage of Cesare Borgia, a ruthless military leader who conquered several parts of the nearby country. In 1503, Leonardo returned to Florence to paint a battle scene on the wall of the Council Hall. The young up-and-coming artist Michelangelo was also commissioned to paint a similar battle scene on another wall, prompting Isaacson to compare and contrast the works of these two great Renaissance artists. Neither man ever finished the project and in 1506, Leonardo returned to Milan. A year later, Leonardo adopted Franceso Melzi as his student, ward, and surrogate son and heir.

From 1508 to 1513, Leonardo focused a great deal on his anatomical studies and dissections. Many of his discoveries would later prove correct but because he did not publish his work, much of it had to be rediscovered by later scientists. His dissections of muscles, bones, ligaments, etc. would also inform his portrayal of the human body in his paintings. Isaacson makes the connection between Leonardo's dissection and analysis of lip and mouth muscles with his ability to paint the Mona Lisa's enigmatic and signature smile. As he studied the human body, Leonardo also studied the body of the earth and the relationship between the two. He began to see the human body as a microcosmic example of the macrocosm of the earth, comparing blood and veins to rivers and tributaries. This led to research in geology, water cycles, astronomy, and more. In 1513, Leonardo moved from Milan to Rome to take advantage of the patronage of the newly elected Pope Leo X. Through his connections with the Pope, Leonardo would meet the new king of France, Francis I who would eventually become his final patron and prompt his move to France.

Toward the end of the book, Isaacson looks at some of Da Vinci's later paintings which all feature a signature pointing gesture. He then analyses the Mona Lisa in depth as the prime example of the culmination of Leonardo's lifetime of work and research across multiple disciplines. Finally, he returns to Leonardo's personal notes and early biographers to surmise what the man's final months and days might have looked like. In conclusion, Isaacson summarizes Leonardo's most admirable traits and significant life themes, encouraging readers to learn from his genius and attempt to emulate his best qualities in their own ways.