<p>Despite extensive theological, political, and biographical study, papal mortality has rarely been examined epidemiologically. The papacy’s unique features, lifelong tenure, late accession, and historically privileged living conditions—make it a distinct case for analyzing historical mortality patterns. The aim of this article was to analyze mortality trends among Popes across nearly two millennia, identifying predominant causes of death and situating these within broader historical, medical, and sociopolitical contexts. Data on 266 recognized Popes, from Saint Peter to Pope Francis, were compiled from ecclesiastical records, biographical dictionaries, and secondary historical sources. Causes of death were classified into natural (infectious, cardiovascular, degenerative), violent (martyrdom, assassination, execution), poisoning, accidents, old age, or unknown. Descriptive statistics summarized age at death, pontificate duration, and era-specific patterns, complemented by narrative contextualization. Natural causes accounted for approximately 71% of deaths, with cardiovascular and cerebrovascular events predominating in the modern era, and febrile illnesses—often linked to plague or malaria—prevalent during the Middle Ages. Violent deaths were concentrated in the early Church, with 28 martyrs among the first 31 Popes. Suspected poisonings occurred most often during the Renaissance. Median age at death rose from 53&#xa0;years in the first millennium to 78&#xa0;years in the modern era, while pontificate durations lengthened markedly after the nineteenth century. Geographically, Italy produced 77% of Popes, underscoring the institutional centrality of Rome. Papal mortality reflects broader epidemiological transitions—from violence and infection to chronic disease—while also mirroring the political and institutional evolution of the Catholic Church. This study contributes to historical epidemiology by demonstrating how leadership, health, and power intersect across two millennia.</p>