To investigate the separate and combined associations of obesity and metabolic syndrome (MetS) with depression and the role of inflammation. Depression was assessed with the Patient Health Questionnaire-9 (PHQ-9) and was defined with a cutpoint of≥ 10. Obesity was defined as body mass index (BMI)≥ 30 kg/m2 from measured height and weight. MetS was defined based on the American Heart Association consensus definition. Participants were divided into four groups: healthy normal weight (MHN), metabolically healthy obese (MHO), metabolically unhealthy normal weight (MUN), and metabolic unhealthy obese (MUO). C-Reactive protein was assessed in a subsample. A total of 18,025 subjects were included in the analysis. Participants with MUO had the highest prevalence of depression compared with the MHN group (14.8% vs. 6.8, p<. 001). While both obesity and MetS were independently associated with depression, there was a significant interaction between the two (p<. 001), indicating that the associations of obesity and MetS with depression were synergistic. After adjusting for baseline characteristics, compared with the MHN group, the MUO group had the highest odds of depression (odds ratio [OR]= 2.30, 95% CI [2.03, 2.61]), followed by MHO group (OR= 1.51, 95% CI [1.30, 1.74]) and the MUN group (OR= 1.39, 95% CI [1.18, 1.64]). The MUO group also showed the highest level of C-reactive protein, and the latter partially mediated the effect between MUO and depressive symptoms (20.5% of the total effect). Both obesity and MetS are associated with depression independent of each other, but when present together, these conditions have a synergistic association with depression.