The United States of America (US) has been profoundly impacted by the Covid-19 pandemic, leading the world in both Covid-19 cases and deaths despite access to vaccinations and advanced treatments. Critical to the US response to Covid-19 from a legal and regulatory perspective is the dichotomy between federal and US state governance powers and systems, which have frequently come into conflict during the pandemic. At the same time, the pandemic occurred during a highly divisive presidential campaign, in which responses became a matter of political rhetoric, and an equally contentious aftermath. The change of presidential administrations in January 2021 brought significant shifts in national policies and rules regarding Covid-19 response and recovery. However, the tensions between national and state legal and regulatory responses remains and continues to be evident in responses to the rise of variants, particularly the Delta variant, across the country. This article reviews Covid-19 legal and regulatory responses and the national and state levels in order to highlight how these entities have addressed economic, social, and public health-related issues.