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During the early months of the U.S. COVID-19 outbreak, the distribution of morbidity and mortality starkly reflected preexisting social determinants of health. Socially vulnerable racial and ethnic populations endured not only the highest number of cases and death rates, but the earliest age mortality. In addition, early government responses to COVID-19 pandemic varied at the state level, while the federal government failed to take immediate policy action to this public health emergency. Drawing from public-use data, we used statistical and econometric modeling techniques to investigate political, structural, and policy determinants of health outcomes during the pandemic. We also investigated the intersecting impacts of these responses on COVID-19 cases in the context of preexisting social vulnerability. Results indicate that partisanship and political ideologies significantly influenced variation in state-level responses. We also found that preexisting social vulnerabilities shaped the observed effectiveness of governmental interventions. Our findings underscore the need to tackle structural vulnerabilities as a more comprehensive policy approach to mitigating the harms of pandemics. Our results also suggest that state governments that resemble inclusive decision-making processes that prioritize the needs of the most impacted communities are more equipped to respond to pandemics. Our study underscores the complex interplay between political dynamics and social determinants of health during a public health emergency, with implications for future pandemic preparedness.