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.

A new choir, radiating chapels, expansions of the transepts, a chapter house, nave aisles and a single-tower western section were all added.

In the summer of 1566, bands of Calvinist iconoclasts visited Catholic churches in the Netherlands, including St. Bavo, shattering stained-glass windows, smashing statues, and destroying paintings and other artworks they perceived as idolatrous.

It is formally known as the Adoration of the Mystic Lamb after its lower centre panel by Hubert and Jan van Eyck.

Frans Pourbus the Elder painted 14 panels representing the History of Saint Andrew (1572) and a Triptych of Viglius Aytta (1571).

[4] Local Ghent painter Petrus Norbertus van Reysschoot painted a series of eleven grisailles, which decorate the choir of the cathedral, above the stalls.

Highlights of the interior decoration of the choir include the Baroque high altar (1702–1782), in white, black, and red flamed marble, and the tomb monuments of Ghent bishops, including that of Antonius Triest, in white and black marble (1652–1654), a major work of Jerôme Duquesnoy (II).

In the choir is the 1559 painting The Queen of Sheba visits King Solomon by the Flemish artist Lucas de Heere.

This allegorical work depicts King Solomon as Philip II of Spain, recognizable by his facial features, receiving gifts from the Queen of Sheba, an allegory of the Low Countries, representing that country donating its riches to the Spanish king in thanks for his prudent government.

In the nave there is an impressive Rococo pulpit (1741–1745), made in oak, gilded wood and white and black marble by Laurent Delvaux, with wrought-iron railings by J. Arens.