Background: The prevalence of obesity is a significant issue in the United States. Among vulnerable populations, obesity exists in the presence of household food insecurity; however the mechanisms of the relationship are not well understood. General perceived stress and general self-efficacy were evaluated as mediators of the relationship between food insecurity and obesity in female heads-of-household with children. Methods: A cross-sectional correlational design with mediation model testing was used. Subjects (N = 86) were recruited through convenience sampling. Data were collected using a demographic questionnaire, the Core Food Security Module (CFSM), the General Perceived Stress Questionnaire (PSQ), and the General Self-Efficacy Scale (SES). Body mass index and waist –to-hip circumference were calculated from measured data. Results: Significant relationships were found between food insecurity and general perceived stress, general perceived stress and obesity, and general self-efficacy and obesity. Mediation models’ testing was not completed due the lack of a significant correlation between food insecurity and obesity. Post hoc analysis was completed using bootstrapping and a revised mediation model process. Conclusion: General perceived stress and general self-efficacy are associated with obesity in female heads-of-household with children who are food insecure. Keywords: Food insecurity, Obesity, Stress, Self-efficacy, Vulnerable populations, Quantitative research, Socioeconomic factors