Objective To investigate whether postmenopausal lipid metabolism disorder is involved in the development of depressive symptoms. Methods Twenty-four LDLR^{-/ -} and sixteen WT C57BL/6J female mice were divided into five groups (n= 8): WT + normal diet group(WT), WT + high-fat diet group(WT-H), ovariectomized LDLR^{-/ -} +normal diet group(LDLR^{-/ -} ), ovariectomized LDLR^{-/ -} + high-fat diet group(LDLR^{-/ -} -H), and ovariectomized LDLR^{-/ -} +high-fat diet + simvastatin group(XF). Mice were fed continuously for 3 months. The postmenopausal lipid metabolism disorder model was established in LDLR^{-/ -} female mice after bilateral ovariectomy combined with a high-fat diet. Body weight, total cholesterol (TC), ERα, and ERβ levels in the hippocampus, depressive behavior, and 5-HT levels in the brain were determined. The correlation between the brain TC level and depression-related indexes was analyzed. Results (1)The LDLR^{-/ -} -H group successfully replicated the characteristics of postmenopausal lipid metabolism disorder, which showed a significant increase in body weight, a notable increase in the brain TC level, and a significant decrease in expression of ERβ in the hippocampus. (2) Horizontal and vertical locomotor activities of the LDLR^{-/ -} -H group were significantly decreased, the immobilized time of TST was significantly increased, and the brain 5-HT level was significantly decreased. (3) The brain TC level of the XF group was significantly decreased, depressive behavior was significantly improved, and the 5-HT level was significantly increased. (4) Correlation analysis showed that the TC level in the brain was significantly correlated to the 5-HT level and depression-like behaviors. Conclusions Postmenopausal lipid metabolism disorder induces depressive symptoms, and depression symptoms can be significantly improved by regulating lipid metabolism disorder.