Accelerating evidence confirms the contribution of per- and polyfluoroalkyl substances (PFAS) to disease burden and disability across the lifespan. Given that policy makers raise the high cost of remediation and of substituting PFAS with safer alternatives in consumer products as barriers to confronting adverse health outcomes associated with PFAS exposure, it is important to document the costs of inaction even in the presence of uncertainty. We therefore quantified disease burdens and related economic costs due to legacy PFAS exposures in the US in 2018. We leveraged systematic reviews and used meta-analytic inputs whenever possible, identified previously published exposure–response relationships, and calculated PFOA- and PFOS-attributable increases in 13 conditions. These increments were then applied to census data to determine total annual PFOA- and PFOS-attributable cases of disease, from which we calculated economic costs due to medical care and lost productivity using previously published cost-of-illness data. We identified PFAS-attributable disease costs in the US of $5.52 billion across five primary disease endpoints shown to be associated with PFAS exposure in meta-analyses. This estimate represented the lower bound, with sensitivity analyses revealing as much as $62.6 billion in overall costs. While further work is needed to assess probability of causation and establish with greater certainty effects of the broader category of PFAS, the results confirm further that public health and policy interventions are still necessary to reduce exposure to PFOA and PFOS and their endocrine-disrupting effects. This study demonstrates the large potential economic implications of regulatory inaction.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12403-022-00496-y.