At that time, to check the spread of Protestantism, Pope Pius IV raised it to the dignity of a see, and made it suffragan to the archdiocese of Mechelen.

When after a long siege the city was captured by Prince Frederick Henry (14 September 1629) and held in the name of the States-General, the sixth bishop, Michael Ophovius, was obliged to abandon his see, which he did in a solemn procession, surrounded by his clergy, and bearing with him a famous miraculous statue of the Blessed Virgin which he placed in safety at Brussels.

By the Treaty of Westphalia (1648) the entire territory of the diocese was recognized as a permanent conquest of the Dutch Republic, and made directly subject to the jurisdiction of the States General.

In 1810 Napoleon had tried to create another diocese under that name, inclusive of the territory known as the Bouches du Rhin, and obtained a titular for the new see in the person of the imperial courtier, Monsignor Van Camp.

The ancient see was finally revived by Pope Pius IX on the occasion of the restoration of the hierarchy in the Netherlands, where, since 1848, the revised constitution has assured Catholics full political and religious liberty.

Jan Zwijsen, a native of the diocese and its most illustrious son, hitherto vicar-Apostolic, was the first bishop of the re-established see, though temporarily he was known as administrator-Apostolic, since he was already Archbishop of Utrecht, with which office he was to unite the government of 's-Hertogenbosch.