Evidence indicates that Leonardo had apprentices and pupils in Milan, for whom he probably wrote the various texts later compiled as Treatise on Painting (1651; translated 1956). The most important of his own paintings during the early Milan period was The Virgin of the Rocks, two versions of which exist (1483-1485, Louvre, Paris; 1490s to 1506-1508, National Gallery, London); he worked on the compositions for a long time, as was his custom, seemingly unwilling to finish what he had begun. From 1495 to 1497 Leonardo labored on his masterpiece, The Last Supper, a mural in the refectory of the Monastery of Santa Maria delle Grazie, Milan. Unfortunately, his experimental use of oil on dry plaster (on what was the thin outer wall of a space designed for serving food) was technically unsound, and by 1500 its deterioration had begun. Since 1726 attempts have been made to restore it. Several of these efforts involved repainting. From 1977 to 1999, a concerted restoration and conservation program made use of the latest technology to reverse some of the damage. Although much of the original surface is gone, the majesty of the composition and the penetrating characterization of the figures give a fleeting vision of its vanished splendor.

During his long stay in Milan, Leonardo also produced other paintings and drawings (most of which have been lost), theater designs, architectural drawings, and models for the dome of Milan Cathedral. His largest commission was for a colossal bronze monument to Francesco Sforza, father of Ludovico, in the courtyard of Castello Sforzesco. In December 1499, however, the Sforza family was driven from Milan by French forces; Leonardo left the statue unfinished (it was destroyed by French archers, who used the terra cotta model as a target) and he returned to Florence in 1500.