The Capuchin Catacombs of Palermo contain over 1800 preserved bodies dating from the 16th to 20th centuries AD and showing evidence of biodeterioration. An extensive microbiological and molecular investigation was recently performed. Samples were taken from skin, muscle, hair, bone, stuffing materials, clothes, and surrounding walls as well as from the indoor air. In this study, we witnessed that the different degradation phenomena observed on the variety of materials located at the Capuchin Catacombs of Palermo are biological in origin. Molecular techniques showed the dominance of halophilic species of the domains Bacteria and Archaea on the walls and – as a result of salt emanating from the walls – on the mummies themselves. Nevertheless, specialized microorganisms belonging to taxa well-known for their cellulolytic and proteolytic activities were detected on clothes and stuffing material, and on skin, muscle, hair, and bone, respectively. This specialized microbiota is threatening the conservation of the mummies themselves. Additionally, sequences related to the human skin microbiome and to some pathogenic Bacteria (order Clostridiales) and fungi (genus Phialosimplex) were identified on samples derived from the mummies. Furthermore, a phosphate-reducing fungus, Penicillium radicum, was detected on bone. Finally, the high concentration of airborne fungal spores is not conducive to the conservation of the human remains and is posing a potential health risk for visitors.