In the early modern period Neuss declined in importance. During the storming of the city by Spanish troops in the conflict known as the Cologne War a fire broke out and destroyed the medieval part of the town.

During the Thirty Years’ War Neuss was occupied by Protestant Hessian troops. In 1672 the French king Louis XIV began building a citadel for which numerous buildings had to be torn down, a project which aggravated the city’s already precarious financial situation. It was only after the period of the Electorate that Neuss experienced an economic upswing with new impulses brought by the French occupation of the Rhineland in 1794. The economic freedom introduced by the French administration stimulated skilled crafts and trades, while the elimination of many tolls following the annexation of the Rhineland into the French empire promoted commerce and made Neuss an important transshipment place for agricultural goods. Nearly all the monasteries and cloisters in the city were closed down, and their possessions seized by the state and sold to private buyers. The economic boom went hand in hand with improvements to infrastructure. After the construction of the Nordkanal, a canal designed to go from Neuss to Antwerp, had failed in the Napoleonic period the Neuss city administration began the expansion of the Rhine port to enable larger ships to call at Neuss. The road network was improved as well. In 1853 Neuss was connected to the Düsseldorf-Aachen railway line. The second half of the 19th century was dominated by industrialization. Numerous industrial enterprises settled in the Neuss port area. They offered work to many people and caused a busy influx of workers from the surrounding area. Around 1900 Neuss had some 30,000 residents.