Food insecurity is prevalent among racial/ethnic minority populations in the US. To date, few studies have examined the association between pre-COVID-19 experiences of food insecurity and COVID-19 infection rates through a race/ethnicity lens. To examine the associations of race/ethnicity and past experiences of food insecurity with COVID-19 infection rates and the interactions of race/ethnicity and food insecurity, while controlling for demographic, socioeconomic, risk exposure, and geographic confounders. This cross-sectional study examined the associations of race/ethnicity and food insecurity with cumulative COVID-19 infection rates in 3133 US counties, as of July 21 and December 14, 2020. Data were analyzed from November 2020 through March 2021. Racial/ethnic minority groups who experienced food insecurity. The dependent variable was COVID-19 infections per 1000 residents. The independent variables of interest were race/ethnicity, food insecurity, and their interactions. Among 3133 US counties, the mean (SD) racial/ethnic composition was 9.0% (14.3%) Black residents, 9.6% (13.8%) Hispanic residents, 2.3% (7.3%) American Indian or Alaska Native residents, 1.7% (3.2%) Asian American or Pacific Islander residents, and 76.1% (20.1%) White residents. The mean (SD) proportion of women was 49.9% (2.3%), and the mean (SD) proportion of individuals aged 65 years or older was 19.3% (4.7%). In these counties, large Black and Hispanic populations were associated with increased COVID-19 infection rates in July 2020. An increase of 1 SD in the percentage of Black and Hispanic residents in a county was associated with an increase in infection rates per 1000 residents of 2.99 (95% CI, 2.04 to 3.94; P < .001) and 2.91 (95% CI, 0.39 to 5.43; P = .02), respectively. By December, a large Black population was no longer associated with increased COVID-19 infection rates. However, a 1-SD increase in the percentage of Black residents in counties with high prevalence of food insecurity was associated with an increase in infections per 1000 residents of 0.90 (95% CI, 0.33 to 1.47; P = .003). Similarly, a 1-SD increase in the percentage of American Indian or Alaska Native residents in counties with high levels of food insecurity was associated with an increase in COVID-19 infections per 1000 residents of 0.57 (95% CI, 0.06 to 1.08; P = .03). By contrast, a 1-SD increase in Hispanic populations in a county remained independently associated with a 5.64 (95% CI, 3.54 to 7.75; P < .001) increase in infection rates per 1000 residents in December 2020 vs 2.91 in July 2020. Furthermore, while a 1-SD increase in the proportion of Asian American or Pacific Islander residents was associated with a decrease in infection rates per 1000 residents of -1.39 (95% CI, -2.29 to 0.49; P = .003), the interaction with food insecurity revealed a similar association (interaction coefficient, -1.48; 95% CI, -2.26 to -0.70; P < .001). This study sheds light on the association of race/ethnicity and past experiences of food insecurity with COVID-19 infection rates in the United States. These findings suggest that the channels through which various racial/ethnic minority population concentrations were associated with COVID-19 infection rates were markedly different during the pandemic.