The cathedral stands on the site of the former Chapel of St. John the Baptist, which was primarily of wooden construction and was consecrated in 942 by Transmarus, Bishop of Tournai and Noyon. Traces of a later Romanesque structure can be found in the cathedral's crypt.[1] Construction of the Gothic church began around 1274.

In the subsequent period from the 14th through 16th centuries, nearly continuous expansion projects in the Gothic style were executed on the structure. A new choir, radiating chapels, expansions of the transepts, a chapter house, nave aisles and a single-tower western section were all added.

In 1539, as a result of the rebellion against Charles V, who was baptized in the church, the old Abbey of St. Bavo was dissolved. Its abbot and monks went on to become canons in a Chapter that was attached to what then became the Church of Saint Bavo. When the Diocese of Ghent was founded in 1559, the church became its cathedral. Construction was considered complete on June 7, 1569.

In the summer of 1566, bands of Calvinist iconoclasts visited Catholic churches in the Netherlands, shattering stained-glass windows, smashing statues, and destroying paintings and other artworks they perceived as idolatrous.[2] However, the altarpiece by the Van Eycks was saved.