Regional variations in coronavirus disease 2019 (COVID-19) suggest non-uniform impacts on health-related quality-of-life (HRQoL) across the US. This study measured regional variations in US population-level HRQoL during COVID-19. HRQoL was measured by the EQ-5D-5L in a three-wave cross-sectional online survey (spring 2020, summer 2020, winter 2021). Adjusted likelihood of any problems in EQ-5D-5L domains and adjusted mean utility and EQ-VAS were estimated and compared between US Census Bureau-designated region-divisions and waves. Regional variations were significant (p < 0.05) in all domains except Pain/Discomfort in spring 2020, Mobility in summer 2020, and Anxiety/Depression in winter 2021. In spring 2020, East South Central (ESC) had the most Mobility (38%) and Usual Activities (66%) problems, while Self-Care problems were greatest in Mountain (53%), and Anxiety/Depression greatest in East North Central (ENC, 72%) and West North Central (80%). In summer 2020, Self-Care problems were again greatest in Mountain (62%), while ENC saw the most Usual Activities (69%), Pain/Discomfort (67%), and Anxiety/Depression (83%) problems. By winter 2021, ESC had the most problems in Mobility (52%), Self-Care (79%), and Pain/Discomfort (79%), with Usual Activities (68%) only second to Middle Atlantic (69%). Both mean utility and EQ-VAS were significantly lowest in ESC in spring 2020 and winter 2021. Otherwise, utility and EQ-VAS trends generally disagreed. HRQoL varied considerably across regions, often worst in ESC. Variation was likely driven by multiple factors including case rates, policies, and preexisting vulnerabilities; these relationships should be explored in future research. Findings support the need for region-specific health interventions.