Obesity and mental health are significant global health concerns. Evidence has linked increased adiposity with depression and well-being; however, there is limited documented evidence in Ireland. Research also suggests lifestyle factors and disease conditions to be related to mental health. These may modulate relationships between adiposity and depression and well-being. This was a cross-sectional study of 1,821 men and women aged 46-73 years, randomly selected from a large primary care centre. Depression and well-being were assessed using the 20-item Centre for Epidemiologic Studies Depression Scale (CES-D) and the World Health Organization-Five (WHO-5) Well-Being Index. Linear regression analyses were performed to examine relationships between mental health scores (dependent variable) and adiposity (independent variable) defined using body mass index (BMI) and waist-height ratio while adjusting for demographic characteristics, lifestyle factors and disease conditions. BMI and waist-height ratio had a significant positive association with depression scores and a significant inverse association with well-being scores in males and females. These associations were maintained following adjustment for demographic variables and lifestyle factors. In final models where disease conditions were adjusted for, BMI (β = 0.743, p < .001) and waist-height ratio (β = 0.719, p < .001) associations with the CES-D score remained significant. In stratified analyses, relationships between measures of adiposity and depression were found to be stronger in females (BMI: β = 0.806, p = .007; waist-height ratio: β = 0.768, p = .01) than males (BMI: β = 0.573, p = .049; waist-height ratio: β = 0.593, p = .044) but no effect modification was identified. These findings suggest that increased adiposity is significantly associated with poorer mental health, independent of lifestyle factors and disease conditions. Targeted interventions for reducing depression should include better population-level weight management measures.