In his Missa Sub tuum presidium, the number of voice parts in the five movements increases from three in the Kyrie, to four in the Gloria, and so on up to seven in the Agnus Dei. The title chant is clearly heard in the top voice throughout the work, and five additional Marian chants are found in movements other than the Kyrie. His late four-voice mass, Missa Maria zart (tender Maria), tentatively dated to around 1504, is based on a devotional song popular in the Tyrol, which he probably heard as he went through the region around 1503 to 1504. Requiring more than an hour to perform, it is one of the longest polyphonic settings of the Mass Ordinary ever written.

While most of Obrecht's appointments were in Flanders in the Low Countries, he made at least two trips to Italy, once in 1487 at the invitation of Duke Ercole d'Este I of Ferrara, and again in 1504. Ercole had heard Obrecht's music, which is known to have circulated in Italy between 1484 and 1487, and said that he appreciated it above the music of all other contemporary composers; consequently he invited Obrecht to Ferrara for six months in 1487. In 1504 Obrecht returned to Ferrara, but on the death of the Duke at the beginning of the next year he became unemployed. In what capacity he stayed in Ferrara is unknown, but he died in the outbreak of plague there just before 1 August 1505.

Obrecht wrote mainly sacred music—masses and motets—and he also wrote some chansons.

Combining modern and archaic elements, Obrecht's style is multi-dimensional. Perhaps more than those of the mature Josquin, the masses of Obrecht display a profound debt to the music of Johannes Ockeghem in the wide-arching melodies and long musical phrases that typify the latter's music. Obrecht's style is an Example of the contrapuntal extravagance of the late 15th century. He often used a cantus firmus technique for his masses: sometimes he divided his source material up into short phrases; at other times he used retrograde versions of complete melodies or melodic fragments. He once even extracted the component notes and ordered them by note value, long to short, constructing new melodic material from the reordered sequences of notes. Clearly to Obrecht there could not be too much variety, particularly during the musically exploratory period of his early twenties. He began to break free from conformity to formes fixes, especially in his chansons. Of the formes fixes, the rondeau retained its popularity longest. However, he much preferred composing Masses, where he found greater freedom. Furthermore, his motets reveal a wide variety of moods and techniques.