He was appointed as ambassador of Venetian Republic at the marriage of Franceso de’ Medici and Bianca Cappello in 1579 and wrote music of celebration for Henry III of France, who visited Venice in 1574.

We can deduce that Merulo used the Steccata's organ for his proofs of new composition, based on his Venetian experience, and continued to compose in this style.

Often his keyboard pieces begin as though they are to be a transcription of vocal polyphony, but then gradually add embellishment and elaboration until they reach a climactic passage of considerable virtuosity.

Sometimes, especially in his later music, he develops ornaments which acquire the status of a motif, which is then used developmentally; this anticipates a principal generative technique in the Baroque era.

His keyboard music was hugely influential, and his ideas can be seen in the music of Sweelinck, Frescobaldi and others; because of the immense influence of Sweelinck as a teacher, much of the virtuoso keyboard technique of the north German organ school, culminating in Johann Sebastian Bach, can claim to be descended from the innovations of Merulo.

Since he was a member of what is known today as the Venetian School, he also wrote motets for double choir in the manner of Andrea and Giovanni Gabrieli.