How Amazonian Indigenous Peoples combatted emergent epidemic diseases in colonial times, and their innovative responses to epidemiological crises, has not received sufficient attention. This study outlines a clash of cultures and an entanglement of places and people related to pandemic diseases and epidemic death in the Eastern Guiana Highlands, northern Amazonia. By means of archival and historical sources, the article provides eyewitness insight into multiple waves of highly contagious epidemics that affected Cariban-speaking communities in Eastern Guiana – Suriname, French Guiana, and Brazilian Amapá – over the past 550 years. The paper commences with some general statements on illness and healing. Hitherto unpublished journal entries by the Governor of Suriname of an outbreak of the pox during the winter of 1743-1744 set the scene, these are followed by rare nineteenth and twentieth century historical accounts, and a novel interpretation of Wayana oral history – posited to be the first account of the spread of a viral disease in Amazonia in July 1542. The paper concludes with responses to the current COVID-19 pandemic from an indigenous etiology which demonstrates indigenous historical consciousness of the social present as related to events from the past.