In a letter dated 1482, found in the Codex Atlanticus at the Ambrosian Library in Milan, Leonardo offers his services to Ludovico il Moro, the guardian of the Duke of Milan Gian Galeazzo, and the true holder of ducal power. In the letter Leonardo presents himself as military engineer, exalting his technical expertise and, only marginally, his artistic talent. In the same letter Leonardo flatters Il Moro by promising to make an equestrian monument in honour of his father Francesco Sforza, the first Duke of Milan.

Leonardo is in fact mentioned in a list of Florentine "merchants" who arrived at the court of Milan after June 15, 1480.

It is highly probable that Leonardo had been summoned to Milan by Ludovico il Moro for the purpose of erecting the monument to Francesco Sforza.

The commission, dated April 25, 1483, for the colouring of the altarpiece dedicated to the Immaculate Conception, conferred by the prior of the Chapel of the Conception in the Church of San Francesco in Milan, seems to confirm the presence of Leonardo at the Sforza court that year. But a clause in the contract specifying that the artist would be allowed to assign others to finish his work in case he left the city suggests that, at this time, his place at Il Moro's court could not be considered definitive.

The history of the Virgin of the Rocks is perturbed by long-drawn-out legal controversy, which concluded only in 1508. The contract between the prior, on the one hand, and Leonardo in association with the De Predis brothers on the other, established that the work on the altarpiece of the Madonna had to be finished by December 8th of the following year. On an attached sheet, written in another hand, the subjects that should be painted on the panel, as well as the colours and techniques to be used were described in detail. The description of the commission does not match either of the two paintings existing today, one in the Louvre, the other in the National Gallery. Art historians have identified the London version as the panel that should effectively have been placed above the altar of the Immaculate Conception in Milan, but its technical details obviously differ from the prescriptions of the contract. Although it is not known whether this discrepancy gave the clients a pretext for not paying their debt, it is instead certain that Leonardo and the De Predis brothers urgently requested payment on several occasions, going so far as to take legal action.

In the years spent in Milan, Leonardo began his study of anatomy and became interested in architecture, participating with a wooden model in the competition for the construction of the lantern on the Milan Cathedral. In 1490 he went to Pavia to offer his services as consultant for the construction of the cathedral to Bishop Ascanio Sforza, brother of Ludovico il Moro.

During these same years he painted several portraits, including the so-called Lady with an Ermine, The Musician and La Belle Ferrovière, supreme examples of Leonardo's studies, now fully developed, on the rendering of "motions of the mind" and on the torsion of the bust.

In 1490 Leonardo started work on the equestrian statue. Only three years later, in 1493, on the occasion of the wedding of Il Moro's daughter and Maximilian of Hapsburg, he presented a clay model of the monument.

During these same years Leonardo made his debut in the role of director of pageants and theatrical set design. He also compiled the first draft of his unfinished Book on Painting.

On the date of July 16, 1493, Leonardo recorded among his notes the arrival in Milan of a certain "Catelina" (Codex Forster III, f.88r), whom art historians tend to identify as his mother. For perhaps less than a year, the woman seems to have lived with her son, until her death, recorded by Leonardo in a list of expenses incurred for her funeral (Codex Forster II, f. 64v).

In 1494, when Charles VIII invaded Italy, Il Moro decided to send the bronze destined to Leonardo's equestrian statue to Ferrara, to be used for cannons. In spite of the turbulent political situation, Leonardo remained in the city, working on the Last Supper, the fresco he had been commissioned to paint in the Dominican monastery of Santa Maria delle Grazie, the Sforza family's mausoleum.

In late 1497 Leonardo completed the Last Supper, hailed by Vasari as a «most beautiful and marvellous thing». The fame bestowed on him by this wall painting undoubted contributed to re-establishing a certain equilibrium in his relations with Il Moro. Nevertheless, when the Duchy of Milan was invaded by Louis XII of France, Leonardo preferred to leave the city.