Food insecurity is a significant public health problem in the United States leading to substantial social, economic, and health care–related burdens. While studies continue to estimate the prevalence of food insecurity, the long-term outcomes are not extensively explored. The purpose of this study was to assess the impact of food insecurity on mortality. We analyzed data on adults (≥ 20 years) from the 1999–2010 National Health and Nutrition Examination Survey, with mortality data obtained through 2015. Among the total study participants (n = 25,247), 17.6% reported food insecurity. Food-insecure individuals were more likely to be younger in age, minorities, poorer, with lesser education, obese, smokers, and with diabetes compared to food-secure counterparts. During a 10.2-year follow-up, among the food insecure, 821 individuals died (11%). The hazard ratio (HR) for mortality among the food insecure compared with the food secure, with adjustment for age and gender only, was 1.58; 95% confidence interval [CI: 1.25, 2.01]. The adjusted HRs for all-cause mortality, HR = 1.46, CI [1.23, 1.72], p < .001, and cardiovascular mortality, HR = 1.75, CI [1.19, 2.57], p < .01, were statistically significantly higher among food-insecure individuals, after adjustment for multiple demographic and health risk factors. Individuals who are food-insecure have a significantly higher probability of death from any cause or cardiovascular disease in long-term follow-up. Comprehensive and interdisciplinary approaches to reducing food insecurity–related disparities and health risks should be implemented. Including food insecurity in health risk assessments and addressing food insecurity as a determinant of long-term outcomes may contribute to lower premature death rates.