Objective: Obesity has been shown to produce a state of systematic low‐grade inflammation that may have detrimental neuropsychiatric effects.Design and Methods:Longitudinal associations between obesity, inflammation, and depressive symptoms amongst a cohort of older English adults over 4 years of follow‐up were examined. Participants were 3,891 obese and non obese people drawn from the English longitudinal study of ageing (ELSA) [aged 64.9 (SD = 8.8) years, 44.6% men]. Depressive symptoms were assessed at baseline and after 4 years of follow‐up using the eight‐item center for epidemiological studies—depression scale (CES‐D).Results:Approximately 26.3% (N = 1,025) of the sample were categorized as obese at baseline. Obesity at baseline was associated with elevated levels of depressive symptoms at follow‐up (P < 0.001), in analyses that adjusted for depression levels at baseline and socio demographic and background variables including the prevalence of permanent illness/disability, alcohol consumption, sedentary behavior, and smoking. In addition, C‐reactive protein (CRP) concentrations at baseline were independently associated with CES‐D depression scores at follow‐up (P = 0.008) in fully adjusted analyses. Subsequent mediation analyses revealed that CRP levels explained ∼20% of the obesity‐related longitudinal change in depression scores. Conclusion:These data suggest that chronic inflammation may be a key determinant of depressive symptoms in obesity.