It was not until 1696 when the court architect Johann Conrad Giesler converted the building to house the Landgrave art and natural history collection.

In 1709 Karl founded the Collegium Carolinum, a scientific research centre with famous scholars Georg Forster and Samuel Thomas von Soemmerring at its core.

A hundred years later when Kassel was a part of Prussia, natural objects were reintroduced into the Ottoneum, which was now under the title of "Preußiches Naturaliemuseum" (The Royal Prussian Kind Museum).

However, in October 1943, during World War II the building was damaged by fire and high explosive bombs, and more than half of the collection was lost.

[6] The Ottoneum is also home to the varied history of the area of Kassel, beginning from the Permian period in the Paleozoic, through the Mesozoic, and finally through to the modern day in the Cenozoic, including the Ice Age.