The series explores the fictitious early life of Leonardo da Vinci during the renaissance in Italy. He is an eccentric genius who has struggled to deal with his inner demons and unruly imagination, as he yearns for legitimacy with his father. Their sometimes antagonistic relationship results in Leonardo working for the House of Medici. While there he becomes embroiled in a political scheme to control Florence, as he hunts for a spy who is revealing information to the Catholic Church and the Pazzi family. He also unknowingly begins an affair with Lucrezia Donati, who is revealed to be the mistress of Lorenzo de' Medici. The series depicts many of Leonardo's inventions and subsequent works as a military engineer for the Duke of Milan and the Borgias.

These events coincide with Leonardo's quest to uncover the Book of Leaves. He is guided by a mystic to unlock the hidden areas of his mind by accessing the Fountain of Memory, as he gets involved with a mysterious cult known as the Sons of Mithras. They inform him that he has the power to not only see the future but to shape it.