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.

When Ludovico asks Leonardo to create an equestrian statue in honor of his father, it stimulates his ambition even more, and the artist strives to exceed the expectations placed on him. While working on the work, Da Vinci places his trust in a person everyone would judge unreliable: Salaì, a resourceful young thief.

Following the death of Ludovico's wife, Leonardo is assigned a new commission but struggles to deal with his inner turmoil; after taking on board some wise words from Fr. Luca Pacioli, Leonardo seeks assistance.

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.