Born in Weert, he lived in Italy from an early age. He was a choir boy at the chapel of Maria di Cardona in Naples, and then was a pupil of Cypriano de Rore at the court of the Este in Ferrara (c. 1550 -1555). Subsequently he was briefly engaged at the courts of Novellara, Mantua and Parma.
In 1565, he entered the service of the Gonzaga in Mantua and became choir master at the ducal chapel of S. Barbara where he stayed until 1592. He was succeeded by Gastoldi.
His private life was stormy, his wife deserted him, and he had an ill-fated love affair with Tarquinia Molza, a singer at the Ferrara court.
De Wert wrote over 230 madrigalss and other secular works (published in 16 volumes 1558-1608), as well as over 150 sacred pieces (motets, hymns etc.) which demonstrate his contrapuntal mastery.
De Wert stands between Cypriano de Rore and Claudio Monteverdi, who worked under him at Mantua and whom he greatly infuenced.
He died in Mantua.