The medieval enceinte has always delimited the perimeter of the city. Following the capture of the city by the Burgundians in 1443, the Duchy became part of the House of Burgundy. Luxembourg became a focus of inter-regional conflicts, most notably between the heir to Burgundy, the Holy Roman Emperor Charles V, and the King of France, François I. The city was conquered twice by the French (1542 and 1544). The ancestral castle of the House of Luxembourg was destroyed and would never be rebuilt. After 1544, the Bock became a strong artillery position. The Altmünster monastery was rebuilt in the Grund. The first bastions – Marie (1546) and Camus (1556) – appeared. Development in artillery accelerated the design of new fortifications, and this was reflected in the fundamental theoretical writings on the art of warfare.

Under Philip II of Spain, the Duchy was administered from Brussels. In Luxembourg, the Renaissance was marked by Governor Peter Ernst von Mansfeld. Leading his troops for the Spanish Crown, he played an active part in the Eighty Years' War. Luxembourg was spared from this conflict, and the Fortress continued to be reinforced.

During the Counter-Reformation, the Spanish government of Luxembourg encouraged the establishment of the Jesuit order, thereby influencing the Catholic orientation of the country. Our Lady of Consolation was proclaimed protectress of the city in 1666 and of the Duchy in 1678.

During the Thirty Years' War (1618-1648), the French laid siege to Thionville, the then border town of the Duchy of Luxembourg. In 1639, Governor Beck managed to relieve the city, but it was finally captured in 1643.

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