Pope Paul III confirmed his appointment on January 27, 1546, and he was consecrated as a bishop by Melchior Zobel von Giebelstadt, Bishop of Würzburg, on May 2, 1546.

The practice of canonical visitation had been re-established by the Council of Trent, so Sebastian conducted a visitation of the Archbishopric of Mainz, aimed at rooting out Protestant tendencies in the archbishopric.

Sebastian held a provincial synod on November 19, 1548 to launch the Counter-Reformation in Mainz.

This convinced Sebastian that Charles V, Holy Roman Empire was unable to protect the ecclesiastical territories from the secular states surrounding them.

He thus became a supporter of the principle of cuius regio, eius religio, although he died before the Peace of Augsburg was signed.