According to the World Health Organization, mental distress and related illnesses are becoming leading causes of morbidity and mortality in developing countries. Despite the influence of food insecurity on mental health, empirical understanding of this relationship in sub-Saharan Africa, where incidence of food insecurity is relatively high, is almost non-existent. This study contributes to the literature by examining the association between food insecurity and mental health in the Upper West Region of Ghana. We used Ordinary Least Square (OLS) to analyze cross-sectional data collected on household heads (n = 1438) in 2014 using the Household Food Insecurity Access Scale and the DUKE Health Profile. The results show that heads of severely food insecure (β = 0.934, p ≤ 0.001) and moderately food secure households (β = 0.759, p ≤ 0.001) were more likely to report elevated mental distress compared to those from food secure households. We also found that female household heads were more likely to report elevated mental distress (β = 0.164, p ≤ 0.05) compared to their male counterparts. Our findings suggest the need to improve food security as a strategy targeted at improving overall mental health in the Ghanaian context.