This article emerged as the human species collectively have been experiencing the worst global pandemic in a century. With a long view of the ecological, economic, social, and political factors that promote the emergence and spread of infectious disease, archaeologists are well positioned to examine the antecedents of the present crisis. In this article, we bring together a variety of perspectives on the issues surrounding the emergence, spread, and effects of disease in both the Americas and Afro-Eurasian contexts. Recognizing that human populations most severely impacted by COVID-19 are typically descendants of marginalized groups, we investigate pre- and postcontact disease vectors among Indigenous and Black communities in North America, outlining the systemic impacts of diseases and the conditions that exacerbate their spread. We look at how material culture both reflects and changes as a result of social transformations brought about by disease, the insights that paleopathology provides about the ancient human condition, and the impacts of ancient globalization on the spread of disease worldwide. By understanding the differential effects of past epidemics on diverse communities and contributing to more equitable sociopolitical agendas, archaeology can play a key role in helping to pursue a more just future.