He was on intimate terms with the emperor John VI Cantacuzene, whom he accompanied in his retirement to a monastery. In 1355 he succeeded his uncle Nilus Cabasilas, like himself a determined opponent of the union of the Greek and Latin churches, as archbishop of Thessalonica.

In the Hesychast controversy he took the side of the monks of Athos and Gregory Palamas.

His chief work is his , in which he lays down the principle that union with Christ is effected by the three great mysteries of baptism, confirmation, and the eucharist. He also wrote homilies on various subjects, and a speech against usurers, printed with other works in Migne, Patrologia Graeca, c. i. A large number of his works is still extant in manuscript.

Cabasilas' major works are Life in Christ and Commentary on the Divine Liturgy. These works display a profound understanding of the sacramental and liturgical life of the Eastern Orthodox Church and are accessible to and instructive for any Christian today worshiping in either the East or West.