Background: Adipokines are considered to be involved in the pathogenesis of diabetes and depression. The associations of serum levels of leptin and irisin with depressive symptoms were investigated in elderly patients with type 2 diabetes (T2DM). Methods: 189 elderly diabetics were assessed with the 30-item Geriatric Depression Scale (GDS-30), and 57 patients with depressive symptoms and 132 controls were selected. Blood biochemical parameters, including serum irisin and leptin, were measured. Results: Serum irisin levels were decreased and leptin concentrations were significantly higher in T2DM patients with depressive symptoms compared to controls. In all subjects, the irisin level was inversely correlated with the leptin level and the GDS-30 score, whereas the leptin level was highly correlated with BMI and the GDS-30 score. Higher levels of leptin and lower concentrations of irisin are, among other factors, variables indicative of predictive capacity for depressive symptoms in elderly patients with T2DM. Conclusions: The results indicated that irisin and leptin levels may be used as diagnostic markers of depressive symptoms in diabetic, elderly patients and as potential therapeutic targets for the treatment. Further prospective and more extensive studies are needed to clarify the role of these adipokines in the common pathogenesis of depression and diabetes.