BACKGROUND: Data on the association between food insecurity and depression in single parents in low- and middle-income countries (LMICs) are limited, and no study has reported the serial mediation effects of psychosocial factors in this association. This study examines the extent to which anxiety and sleep serially explain the food insecurity and depression link among single parents in Ghana. METHODS: Data on 627 single parents were obtained through a multi-stage stratified sampling technique. Food insecurity was assessed using the Food and Agriculture Organization Food Insecurity Experience Scale (FIES), and depression was assessed using the Center for Epidemiological Studies Depression Scale (CES-D-10). Multivariable OLS models and bootstrapping serial mediation analyses were performed to evaluate the hypothesized associations. RESULTS: The mean age (SD) was 45.0 (14.7) years; 67.3% females. After full adjustment, food insecurity was significantly associated with increases in anxiety symptoms (β = 0.61, 95%CI = 0.476 - 0.737), sleep problems (β = 0.04, 95%CI = 0.02 - 0.07), and depression (β = 0.24, 95%CI = 0.12 - 0.36). Food insecurity indirectly related to depression via anxiety (β = 0.35, 95%CI = 0.26-0.44) representing 55.8%, sleep (β = 0.03, 95%CI = 0.0032-0.0575) suggesting 4.0%, and anxiety→sleep (β = 0.013, 95%CI = 0.0024-0.0265) yielding 2.0% of the total effect. CONCLUSIONS: Food insecurity was positively associated with depression. This association was partially and serially explained by generalized anxiety and sleep problems. Efforts to address depression among single parents should consider interventions for food insecurity and psychosocial problems, particularly in LMICs.