In 1457, the first Plague House opened in Leiden. However, the city of Leiden decided in 1635 that the plague house should be located outside the city walls. But its construction took longer than planned. Only in 1661 was the building completed and by then the plague epidemic was already at its end. So, no plague patients were treated in the building we know as Plague House.

But, that does not mean that the building was never used. Over the years, it has had various functions: among others, the building housed a military hospital, a hospital, a state correctional institution, a women's prison and, in 1930, a 'psychopath asylum'. In 1941, the character of the building changed and a museum moved in: the Royal Dutch Army and Weapons Museum 'General Hoefer'.

From 1998, the Pesthuis became the entrance to museum Naturalis.
During the museum's renovation, the Pesthuis even briefly became Trix's house (Naturalis famous T-rex).