The purpose of this study was to examine socio-demographic and health-related factors associated with food insecurity and the association between food insecurity and COVID-19 infection using a nationally representative sample in the U.S. Cross-sectional data of 61,050 adults (≥18 years) from the 2020 and 2021 National Health Interview Survey were analyzed. Food insecurity was measured by the 10-item U.S. Department of Agriculture (USDA) Food Security Survey Module. Weighted multivariable logistic regression models were used to estimate associations with food insecurity. 6.8% of the NHIS participants lived in food-insecure households, and 18.9% tested positive for COVID-19 infection. Young (18-34 years) or middle age (35-64 years), female sex, minor race/ethnicity (Hispanic/non-Hispanic Black/non-Hispanic Asian/others), education level less than high school, unmarried status, unemployment, poverty (below the federal poverty level), having no health insurance, a larger number of adults and children in the household, poorer self-reported health status, and presence of chronic conditions were significantly associated with food insecurity (AOR ranged from 1.20 to 3.15, all p<0.0001). Food insecurity was independently associated with positive COVID-19 infection (AOR=1.25, 95% CI: 1.11, 1.40) controlling for socio-demographic and health-related factors. The greatest magnitude of the association was observed for the non-Hispanic Blacks (AOR=1.47, 95% CI: 1.15, 1.88), females (AOR=1.44, 95% CI: 1.20, 1.71), and those below the federal poverty level (AOR=1.39, 95% CI: 1.12, 1.73) across all the subgroups. Food insecurity disproportionately affected vulnerable subgroups such as young adults, females, minor race/ethnicity groups, and those with lower socioeconomic backgrounds and was associated with positive COVID-19 infection. Policies addressing food insecurity may help reduce the likelihood of COVID-19 infection, especially for those vulnerable subgroups.