Milan, 1506. Leonardo is arrested for poisoning Caterina de Cremona. After protesting his innocence to Stefano Giraldi, Leonardo remembers back to his days as an apprentice in Andrea del Verrocchio's studio, where he first meets Caterina.

With Leonardo's successes recognised and his reputation growing, a risky decision sets to destroy everything he has worked for. Leonardo receives support through new commissions (the Portrait of Ginevra de Benci and The Adoration of the Magi), but pays the price for his actions.

Leonardo ventures to Milan with a determination to claim an offer of patronage from the Duke Regent, Ludovico Sforza. When the reality of the situation turns out to be less appealing and he is assigned to produce a big theatrical entertainment instead of a painting, a newfound relationship helps liberate Leonardo's imagination.

When Ludovico asks Leonardo to create a sculpture in honour of his father, Leonardo's ambitions rise as he tries to outperform. During the work, Leonardo finds himself in Gian Galeazzo Sforza, the young duke of Milan and puts trust in an unexpected source, Salaì, a resourceful thief. As he gets distracted from Caterina, Leonardo ends up in a race against time with a costly decision to make.

After the death of Ludovico's wife, he is given a new art commission but struggles with inner turmoil. After reflecting on wise words from Father Luca Pacioli, Leonardo seeks assistance from friends and presses on with the work, despite tensions in the city. Putting his creativity to the test and experimenting with a new technique, he must deal with the consequences of his actions and results.

Returning to Florence, an uninspired Leonardo accepts to paint the portrait of Lisa Gherardini, that will become the Monna Lisa. After failing to repair his relationship with Caterina, Leonardo goes to Imola, where he receives much praise from his employer, Cesare Borgia.

Reunited with Caterina, Leonardo perseveres with his work but is frustrated by the growing success of a younger artist, Michelangelo. Putting his feelings aside, Leonardo is persuaded to accept a new commission, a giant fresco of the Battle of Anghiari, but faces competition from his newfound rival.

Time is short as Stefano races to save Leonardo and uncovers his secret. With facts and no evidence, an epiphany leads Stefano going to a remote source for help. As the execution nears, Leonardo's life hangs by a thread. His guilt is upheld, and hope seems lost. Holding the fate of Milan's greatest artist in his hands, Stefano realises the answer he seeks lies in the man he is striving to save.