In Milan, in 1506, Leonardo da Vinci is arrested on charges of having poisoned Caterina da Cremona. After declaring his innocence to Stefano Giraldi, an official of the Podestà, Leonardo recalls his days as an apprentice in the workshop of Andrea del Verrocchio, where he first met the model Caterina.

As Leonardo's achievements are recognized and his reputation grows, one risky decision could destroy everything he has worked for. When an unforeseen situation further undermines his reputation as an artist, he sets his sights on the Duchy of Milan and leaves Florence.

Returning to Florence, an uninspired Leonardo accepts to paint the portrait that will become the Mona Lisa; after failing to repair his relationship with Caterina, Leonardo goes to Imola, where he receives much praise from his employer.

Having found Caterina, Leonardo continues his work, but is frustrated by the growing success of a younger artist, Michelangelo Buonarroti. Putting his feelings aside, Leonardo allows himself to be persuaded to accept a new commission.