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.

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.

With time running out, Stefano races to save Leonardo and finally discovers the truth behind his biggest kept secret; armed with the facts but lacking the evidence, an unexpected revelation leaves Stefano turning to an unlikely source for help.