In 1471 he went to Milan, where he joined the singers of the Sforza chapel, which included Johannes Martini, Alexander Agricola, and Loyset Compère.
Weerbeke then joined the papal choir in Rome under Sixtus IV and Innocent VIII, where he remained until 1489, at which time he returned to Milan.
He was almost alone among the Franco-Flemish composers in avoiding the smooth, imitative polyphonic style which was developing at the time, best exemplified by the music of Josquin des Prez.
In style, much of his motet writing is homophonic, incorporating some of the lightness of the contemporary Italian secular music.
His music was much esteemed, especially in Italy, where it represented perhaps the popular aesthetic as opposed to the contrapuntal, but foreign grandeur of most of the composers from the Low Countries.