The study is a presentation of the sole written testimony of the great plague epidemic that struck the island of Rhodes in 1498, at the time when the Order of the Knights of St. John was settled there. The Greek poem "The Thanatikon (i.e., plague) of Rhodes", which was written by Emmanuel Georgillas Limenitis in the late 15th century and recounts the terrible events of the epidemic, was used as a source of information. Among the 644 verses of the poem, elements like the place, time, duration and how the epidemic spread can be identified. Within the historical context of the era, evaluation and analysis of the data reveal the correlation between human activities and the physical history of the disease in the Mediterranean during the 15th century. The Plague of Rhodes confirms the value of non-medical sources in the medico-historical and historico-epidemiological study of the evolution of the disease caused by Yersinia pestis while highlighting an enduring intrinsic weakness of surveillance systems. Despite modern means of epidemiological surveillance, the risk of relaxation of a health system after a long period of absence of an infectious disease constitutes a major factor for future resurgence of the specific disease.