The current manuscript has two aims. First, we examined whether race and ethnicity, perceived discrimination, medical mistrust, and other demographic factors were predictors of COVID-19 vaccine hesitancy and vaccine behavior. Second, we sought to assess whether medical mistrust and perceived discrimination mediate the relationship between race and ethnicity and vaccine behavior. Specifically, we hypothesized that individuals of color had increased COVID-19 vaccine hesitancy as compared to White individuals and perceived discrimination and medical mistrust mediated this relationship. Results revealed that when accounting for sociodemographic characteristics and COVID-19-related variables those with greater medical mistrust were more likely to have vaccine hesitancy. Additionally, after accounting for medical mistrust, Black non-Hispanic/Black Hispanic/White Hispanic individuals had lower odds of having the COVID-19 vaccine compared to White non-Hispanic individuals. Furthermore, combined perceived discrimination and medical mistrust indirectly mediated the relationship between race and ethnicity and having the COVID-19 vaccine. The findings of this study indicate the need for public health efforts to address sentiments of medical mistrust and experiences of perceived discrimination when combating COVID-19 vaccine hesitancy, especially within communities of color.