He engaged in an unprecedented negotiation with the Papacy to create his own rite for Mantua, and devoted considerable resources to developing a musical repertoire for the church, commissioning works by Giaches de Wert and Palestrina.

Part of his correspondence with Palestrina discusses the work commissioned in detail, stipulating Guglielmo's requirements, and therefore giving a sense of his musical preferences.

He enjoyed imitative contrapuntal music but was concerned to maintain clarity of text, thereby showing the influence of Tridentine reforms.

Three months before his death, Gonzaga wounded the organist of the ducal basilica, Ruggier Trofeo, in an encounter over a woman; the latter survived his injuries.

[2] On 26 April 1561 William married Eleonora of Austria, sixth daughter of Ferdinand I, Holy Roman Emperor and Anna of Bohemia and Hungary.