Critical historical analysis of the 19th-century cholera and 21st-century coronavirus-19 (COVID-19) pandemics suggests that in conflicts over pandemic-mitigation policies, the professional backgrounds of principal opponents reveal dominant and minority scientific paradigms, presaging possible epistemological shifts. Epistemic conflict over cholera helped spur biomedical expertise as the dominant paradigm for U.S. public health science and policy beginning in the 20th century. This paradigm was reflected in federal government reliance on infectious disease physicians as the primary scientific decision makers in the COVID-19 pandemic. Similarly, epistemic conflict over challenges to behavioral and social well-being in 2020 may highlight discordance between the dominant biomedical paradigm used in making federal policy and the inherently holistic impact of that policy on population health, suggesting need for a new paradigm of multidisciplinary scientific engagement. Because population-wide public health initiatives affect many aspects of health—physiological, psychological, behavioral, and social—that are best measured and interpreted by experts in these respective fields, multidisciplinary scientific engagement would facilitate optimal, holistic evaluation of policy benefits and harms. This multidisciplinary approach, analogous to that currently recommended in medical management of chronic disease, would advance epidemiological research to inform evidence-based policy for public health crises in which U.S. population-wide interventions are contemplated.