© 2016 American Journal of Preventive Medicine Introduction States in the Mid-South region are among the least healthy in the nation. This descriptive study examines sociodemographic differences in the distribution of chronic diseases and health-related behaviors in the Mid-South versus the rest of the U.S., identifying subgroups at increased risk of chronic disease. Methods Data were obtained from the 2013 Behavioral Risk Factor Surveillance System; analyses were completed in January 2016. Twelve chronic health conditions were assessed: obesity, diabetes, high blood pressure, coronary heart disease, myocardial infarction, stroke, chronic kidney disease, cancer, arthritis, asthma, chronic obstructive pulmonary disease, and depression. Evaluated health-related behaviors included smoking, physical activity, and fruit and vegetable consumption. Age-standardized percentages were reported using complex survey design parameters to enhance generalizability. Results The Mid-South population had increased rates of chronic disease and worse health-related behaviors than the rest of the U.S. population. Mid-South blacks had the highest percentages of obesity, diabetes, high blood pressure, and stroke of all subgroups, along with lower physical activity and fruit and vegetable consumption. In both races and regions, individuals with lower income and education had higher rates of chronic disease and unhealthy behaviors than those with higher income and education. However, black men in both regions had higher obesity and cancer rates in the higher education category. In general, education-level disparities were more pronounced in health-related behaviors, whereas income-level disparities were more pronounced in chronic health conditions. Conclusions Future studies should test tailored interventions to address the specific needs of population subgroups in order to improve their health.