<p>The late Ming and early Qing dynasties were among the periods with a high incidence of infectious diseases in Chinese history. In this study, we aimed to analyze historical data to investigate the geographical factors and disease spectrum of infectious diseases during that time. Our objective was to provide insights for the modern prevention and control of infectious diseases. We collected and organized historical materials from this period. Descriptive statistical methods were used to explore the correlation between epidemics and natural factors. Furthermore, we collected traditional Chinese medicine prescriptions for preventing and treating infectious diseases during this period. By predicting potential diseases treatable through core prescriptions, we aimed to clarify the disease spectrum of epidemics. Cluster analysis results showed that among geographical factors such as famine, drought, and locusts, as well as social phenomena such as wars and inflation, drought had the highest clustering value and the strongest correlation with other factors. Disease spectrum analysis revealed three common types of drug combinations used to treat epidemics: Rheum officinale-ginger-aurantium fruit-magnolia bark-mirabilite, licorice-anemarrhena root-ginseng-poria-atractylodes, and white peony root-licorice-ginger-Chinese angelica-bupleurum. Diseases with a high degree of enrichment for these drugs included Kaposi’s sarcoma-associated herpesvirus infection, human cytomegalovirus infection, and hepatitis B. During the late Ming and early Qing dynasties in China, epidemics occurred frequently and were closely related to factors such as drought, locusts, war, and inflation. The epidemics likely involved a combination of various infectious diseases, including Kaposi’s sarcoma-associated herpesvirus infection, human cytomegalovirus infection, and hepatitis B.</p>