In 1481 Zenale was already a qualified master and a member of Milan's Scuola di San Luca, the painters' guild. He spent much of his career in Milan, collaborating on paintings for the city's churches between 1485 and 1493.
In 1502 Zenale completed the central panel of the Virgin and Child for an altarpiece for the Scuola di Santa Maria at Cantù, near Como, which shows the solid construction and calm beauty characteristic of his art. Early on, he was influenced by Ferrarese masters such as Ercole de' Roberti, but by 1500, Leonardo's presence in Milan influenced his work. By 1513 Zenale seems to have begun devoting himself more to architecture than to painting. In 1519 he was elected architect of the Milan Cathedral, and he became chief architect in 1522. He also wrote a treatise on the theory of perspective. Zenale owned two houses and some land outside of Milan, indicating that he was probably a wealthy man.