The COVID-19 pandemic is the greatest global public health crisis since the 1918 influenza outbreak. As of early June, the novel coronavirus has infected more than 6.3 million people worldwide and more than 1.9 million in the United States (US). The total number of recorded deaths due to COVID-19 are growing at an alarming rate globally (3383,000) and nationally (3109,000) Evidence is mounting regarding the heavier burden of COVID-19 infection, morbidity, and mortality on the underserved populations in the US. This commentary focuses on this global health pandemic and how mitigation of the virus relies heavily on health behavior change to slow its spread, highlighting how the pandemic specifically affects the most socially and economically disadvantaged populations in the US. The commentary also offers short, intermediate and long-term research and policy focused recommendations. Both the research and policy recommendations included in this commentary emphasize equity-driven: (1) research practices, including applying a social determinants and health equity lens on monitoring, evaluation, and clinical trials activities on COVID-19; and (2) policy actions, such as dedicating resources to prioritize high-risk communities for testing, treatment, and prevention approaches and implementing organizational, institutional, and legislative policies that address the social and economic barriers to overall well-being that these populations face during a pandemic. It is our hope that these recommendations will generate momentum in delivering timely, effective, and lifesaving changes.