Public health, personal/community health behaviors, health care delivery, and the scientific community have all been impacted by the COVID-19 pandemic and are consequently poised to consider substantial paradigm shifts that will enhance disease prevention and public health resilience. The current analysis compares the newly developed Lifestyle Health Index (LHI) to U.S. county-level COVID-19 vaccination, infection, and mortality rates. We linked Centers of Disease Control PLACES, the U.S. Community Profile Report, and Nationhood lab databases through common zip-code identifiers to determine the association between county-level LHI scores and COVID-19 outcomes and vaccination status against the backdrop of U.S. regions with distinct cultural phenotypes. There was a statistically significant relationship between a poor LHI, lower COVID-19 vaccination rates and higher COVID-19 infection and mortality rates. There were clear differences in outcomes across the U.S. regions, suggesting distinct regional cultural characteristics may significantly influence health behaviors and outcomes. In the U.S., a syndemic comprising unhealthy lifestyle, chronic disease, and COVID-19 resulted in unnecessary hospitalizations and deaths. Politicization of the pandemic, socioeconomic inequity and regional cultural values meaningfully contributed to the uneven distribution of poor outcomes during this syndemic. Components of the syndemic were avoidable and should not be repeated. Condensed Abstract: The unhealthy lifestyle - chronic disease - COVID-19 U.S. syndemic resulted in unnecessary hospitalizations and deaths. Politicization of the pandemic, socioeconomic inequity and regional cultural values meaningfully contributed to the uneven distribution of poor outcomes during this syndemic. Components of the syndemic were avoidable and should not be repeated.