Description: Background: Patients with major depressive disorder have a higher prevalence and incidence of dyslipidemia. However, clinical studies concerning the association between lipid levels and depression are inconsistent. Adipokines (like leptin and adiponectin) and ghrelin are strongly associated with lipid metabolism. Fish oil, which is reported to possess antidepressant effect, also have beneficial effects on lipid metabolism and the cardiovascular system. In the present study, we investigated lipid metabolism in rats exposed to chronic unpredictable mild stress (CUMS) and the effect of fish oil on lipid profiles, aforementioned adipokines and ghrelin. Methods: Sucrose preference test (SPT), open field test (OFT) and forced swimming test (FST) were used to evaluate the antidepressant-like effects of fish oil. After the behavior tests, peripheral blood were collected. Serum parameters, including fasting triglyceride (TG), total cholesterol (TCH), high density lipoprotein-cholesterol (HDL-c), low density lipoprotein-cholesterol (LDL-c), free fatty acid (FFA), glucose (GLU), adipokines (leptin, adiponectin) and ghrelin were assayed. Results: After 5 weeks of CUMS procedures, rats were induced to depressive-like state, and exhibited increased serum levels of TCH, HDL-c, FFA and decreased serum levels of leptin and ghrelin, whereas the serum status of adiponectin, GLU, TG and LDL-c remained stable. Fish oil treatment showed robust antidepressant effect and reversed the stress-induced lipid disturbance and decrease in serum concentration of ghrelin. Conclusions: Our results suggested that CUMS altered the serum levels of lipid profiles, leptin and ghrelin in rats. Fish oil supplementation not only provided antidepressant-like effects, but also reversed the altered lipid profiles and ghrelin level in serum. Our data indicated that fish oil treatment exerts anti-depressant effect and regulates lipid disturbance simultaneously.