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Background Most studies on health disparities during the coronavirus disease 2019 (COVID-19) pandemic focused on reported cases and deaths, which are influenced by testing availability and access to care. This study aimed to examine severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody seroprevalence in the United States and its associations with race/ethnicity, rurality, and social vulnerability over time. Methods This repeated cross-sectional study used data from blood donations in 50 states and Washington, DC, from July 2020 through June 2021. Donor zip codes were matched to counties and linked with Social Vulnerability Index (SVI) and urban-rural classification. SARS-CoV-2 antibody seroprevalences induced by infection and infection-vaccination combined were estimated. Association of infection-induced seropositivity with demographics, rurality, SVI, and its 4 themes were quantified using multivariate regression models. Results Weighted seroprevalence differed significantly by race/ethnicity and rurality, and increased with increasing social vulnerability. During the study period, infection-induced seroprevalence increased from 1.6% to 27.2% and 3.7% to 20.0% in rural and urban counties, respectively, while rural counties had lower combined infection- and vaccination-induced seroprevalence (80.0% vs 88.1%) in June 2021. Infection-induced seropositivity was associated with being Hispanic, non-Hispanic Black, and living in rural or more socially vulnerable counties, after adjusting for demographic and geographic covariates. Conclusions The findings demonstrated increasing SARS-CoV-2 seroprevalence in the United States across all geographic, demographic, and social sectors. The study illustrated disparities by race-ethnicity, rurality, and social vulnerability. The findings identified areas for targeted vaccination strategies and can inform efforts to reduce inequities and prepare for future outbreaks. [ABSTRACT FROM AUTHOR]