Objectives. To determine the prevalence of COVID-19-related discrimination among major US racial/ethnic groups and estimate associations between discrimination, race/ethnicity, and other sociodemographic characteristics. Methods. We conducted a nationally representative online survey of 5500 American Indian/Alaska Native, Asian, Black/African American, Hawaiian/Pacific Islander, Latino (English and Spanish speaking), White, and multiracial adults from December 2020 to February 2021. Associations between sociodemographic characteristics and COVID-19-related discrimination were estimated via multinomial logistic regression. Results. A total of 22.1% of the participants reported experiencing discriminatory behaviors, and 42.7% reported that people acted afraid of them. All racial/ethnic minorities were more likely than White adults to experience COVID-19-related discrimination, with Asian and American Indian/Alaska Native adults being most likely to experience such discrimination (discriminatory behaviors: adjusted odd ratio [AOR] = 2.59; 95% confidence interval [CI] = 1.73, 3.89; and AOR = 2.67; 95% CI = 1.76, 4.04; people acting afraid: AOR = 1.54; 95% CI = 1.15, 2.07; and AOR = 1.84; 95% CI = 1.34, 2.51). Limited English proficiency, lower education, lower income, and residing in a big city or the East South Central census division also increased the prevalence of discrimination. Conclusions. COVID-19-related discrimination is common, and it appears that the pandemic has exacerbated preexisting resentment against racial/ethnic minorities and marginalized communities. Efforts are needed to minimize and discredit racially driven language and discrimination around COVID-19 and future epidemics. (Am J Public Health. 2022;112(3):453-466. https://doi.org/10.2105/AJPH.2021.306594).