Background: This study aimed to investigate gender-specific associations between food insecurity (FI) and circadian syndrome (CircS) among US adult, and to explore whether body mass index (BMI) and systemic inflammation [white blood cell (WBC) count] mediate these associations. Methods: Cross-sectional data from 12, 601 participants (≥20 yers) in the National Health and Nutrition Examination Survey (NHANES) 2005–2016 survey were analyzed. FI was assessed using the United States Department of Agriculture food security scale module. CircS was defined as the presence of ≥4 of the following components: central obesity, hypertension, elevated fasting glucose, reduced HDL-C, elevated triglycerides, short sleep duration, and depressive symptoms. Finally, weighted logistic regression and mediation analyses were performed to evaluate associations between FI and CircS, and the mediating roles of BMI and WBC count. Results: FI was significantly associated with increased odds of CircS [Adjusted odds ratio (AOR)]: 1.46; 95% confidence interval [CI]: 1.26–1.70), particularly among women (AOR: 1.69; 95% CI: 1.39–2.05). BMI and WBC count partially mediated this relationship in women, accounting for 37.5% and 18.6% of the total effect, respectively. Conclusions: The findings highlight the role of metabolic and inflammatory dysregulation, particularly among women, as potential mechanisms linking FI and circadian health disturbances. Targeting FI through public health strategies that address these pathways may reduce the burden of CircS and related condition, and support the integration of circadian health into nutrition and chronic disease prevention policies.