By 1433 most of the Belgian and Luxembourgian territory along with much of the rest of the Low Countries became part of Burgundy under Philip the Good. When Mary of Burgundy, grand-daughter of Philip the Good married Maximilian I, the Low Countries became Habsburg territory. Their son, Philip I of Castile (Philip the Handsome) was the father of the later Charles V. The Holy Roman Empire was unified with Spain under the Habsburg Dynasty after Charles V inherited several domains.

Especially during the Burgund period (the 15th and 16th centuries), Ypres, Ghent, Bruges, Brussels, and Antwerp took turns at being major European centers for commerce, industry (especially textiles) and art. The Flemish Primitives were a group of painters active primarily in the Southern Netherlands in the 15th and early 16th centuries (for example, Van Eyck and van der Weyden). Flemish tapestries hung on the walls of castles throughout Europe.

The Spanish Netherlands

The Pragmatic Sanction of 1549, issued by Charles V, established the Seventeen Provinces (or Spanish Netherlands in its broad sense) as an entity separate from the Empire and from France. This comprised all of the Netherlands, Belgium, and Luxembourg except for the lands of the Bishopric of Liege.

Eighty Years' War

However, the northern region now known as the Netherlands became increasingly Protestant (i.c. Calvinistic), while the south remained primarily Catholic. The schism resulted in the Union of Atrecht and the Union of Utrecht. When Philip II, son of Charles ascended the Spanish throne, he tried to abolish all Protestantism. Portions of the Netherlands revolted, beginning the Eighty Years' War between the Netherlands and Spain. For the conquered Southern Netherlands the war ended in 1581 with the Fall of Antwerp. This can be seen as the start of Belgium as one region. That same year, the northern Low Countries (i.e. the Netherlands proper) seized independence in the Oath of Abjuration (Plakkaat van Verlatinghe) and started the United Provinces and the Dutch Golden Age. For them, the war lasted until 1648 (the Peace of Westphalia), when Spain recognized the independence of the Netherlands, but held onto the loyal and Catholic region of modern-day Belgium which was all that remained of the Spanish Netherlands.

Southern Netherlands

While the United Provinces gained independence, the Southern Netherlands remained under the rule of the Spanish Habsburgs (1519-1713).

Until 1581 the history of Belgium (except the Bishopric of Liege), the grand-duchy of Luxembourg and the country the Netherlands is the same: they formed the country/region of the Netherlands or the Low Countries. In Dutch, a distinction still exists between on the one hand 'de Nederlanden' (plural, the Low Countries) and 'Nederland' (singular, the present-day state of the Netherlands) that is a consequence of this separation in the 17th century. Before 1581, the Netherlands refers to the Lowlands (De Nederlanden).

During the 17th century Antwerp was still a major European center for commerce, industry and art. The Brueghels, Peter Paul Rubens and Van Dyck's baroque paintings were performed during this period.