The Thirty Years' War also left deep scars and devastation in Wiesbaden. Although the Protestant sovereign initially tried to remain neutral, the city was repeatedly and permanently involved in the turmoil of war.

As early as August 1620, Spanish troops passed through the region. The people of Wiesbaden had acquired a "Salva guardia", a letter of protection, which the enemy troops paid dearly for with natural supplies. In the following years, imperial, Spanish, Swedish (1631/32) and other troops marched through and forced payments in kind or plundered the town. As Count Johannes zu Nassau-Idstein and Wiesbaden joined the initially victorious Swedish side, he had to flee when imperial troops returned after the Swedish defeat and took revenge. In 1637, Wiesbaden became part of Mainz for ten years, but the archbishop is said not to have seriously infringed on religious freedom in Wiesbaden.

The year 1644 is regarded as the absolute "low point" in Wiesbaden's town history, when Bavarian troops again issued the town with a "letter of protection", but still systematically plundered it and mistreated the remaining inhabitants; all surviving inhabitants are said to have left the town. Some returned reluctantly. In 1646, the town once again had to pay a contribution, which was enforced by Captain Engelheimer.

When Count Johannes of Nassau returned shortly before the end of the war in 1647, there were only 51 citizens left to pay homage to him on the market square. The town may still have had a few hundred inhabitants. Rabbits and hens are said to have nested in the hedges and bushes on the market square. The bathhouses were in a bad state, many houses had collapsed and the town fortifications were completely desolate. It took decades for Wiesbaden, like many other German cities, to recover to some extent from the catastrophe of the war.

In the second half of the 17th century, the princes of Nassau were somewhat successful in wooing "new countrymen" from abroad, for example by offering a new home to French religious refugees (the Huguenots), especially west of Frankfurt and in what is now northern Hesse. This policy was quite successful.

It is not known to what extent Wiesbaden was also affected by these "peopling measures" and whether the recruitment attempts, which advertised generous tax breaks and the like for new settlers in Wiesbaden, were really successful. In any case, Wiesbaden's population did not increase significantly at the end of the 17th and 18th centuries. Wiesbaden remained a rather insignificant farming town until the beginning of the 19th century. This only changed when it became the capital of the Duchy of Nassau.