In 2009, an archaeological intervention in the Valle da Gafaria (Lagos, Portugal) allowed the excavation of part of a leprosarium and an associated necropolis (15th–17th centuries). The individuals recovered were buried directly in the soil, in positions and orientations discordant to the prevailing Christian rules. The sample is made up of eleven adult individuals of both sexes. This paper discusses the differential diagnosis of unusual and distinct pathological changes in five of the individuals recovered. The differential diagnosis of the lesions gave rise to several possible pathological conditions, namely, leprosy, treponematosis, brucellosis, slipped femoral capital epiphysis, and Legg-Calvé-Perthes disease. Various macroscopic and radiological aspects led us to consider leprosy as the most probable diagnosis in two individuals. Treponematosis and brucellosis were the probable diagnosis in other two individuals, respectively. One individual presented lesions in the right femur compatible with Legg-Calvé-Perthes disease. Historical documents suggest that the poor, mentally disabled, and people suffering from syphilis, tuberculosis, among others, were also housed in leprosaria. Therefore, it is possible that evidence of other conditions is found in human remains uncovered at a leprosarium. The cases under study enrich the scanty osteoarchaeological documentation of palaeopathology in Portugal in the Modern Age, namely of leprosy, brucellosis, treponematosis, and Legg-Calvé-Perthes disease, and they can contribute to reduce the discrepancy between historical and biological evidences of disease.