Objective To explore the relationship between serum ferroptosis-related indexes and cognitive impairment in postmenopausal women. Methods A total of 148 women were selected from Department of Neurology of The First Affiliated Hospital of Naval Medical University (Second Military Medical University) from Aug. 2019 to Dec. 2021, including 22 cases in reproductive group, 11 in perimenopausal group, and 115 in postmenopausal group. The general information and serum ferroptosis-related indexes (glutathione peroxidase 4[GPX4], reduced glutathione[GSH], cystine/glutamate antiporter[system Xc^-], acyl-CoA synthetase long-chain family member 4[ACSL4], reactive oxygen species (ROS), lipid hydroperoxide[LPO], and malondialdehyde[MDA]) of the 3 groups were compared. According to Montreal cognitive assessment (MoCA) score, the postmenopausal women were divided into cognitive impairment group (n=77) and non-cognitive impairment group (n=38). The levels of the serum ferroptosis-related indexes were compared between the 2 groups. Multiple logistic regression model was used to analyze the influencing factors of cognitive impairment in postmenopausal women. Receiver operating characteristic (ROC) curve was used to analyze the diagnostic value of the influencing factors for cognitive impairment in postmenopausal women. Results Compared with the reproductive and perimenopausal groups, the MoCA score of the postmenopausal group was significantly lower (both P<0.05). The serum levels of system Xc^-, GPX4, GSH, ACSL4, ROS, LPO and MDA were gradually increased in the reproductive, perimenopausal and postmenopausal groups, and the differences were significant (all P<0.001). Compared with the noncognitive impairment group, the educational years of the postmenopausal women was significantly shorter in the cognitive impairment group, and serum levels of system Xc^-, GPX4, GSH, ACSL4, ROS, LPO and MDA were significantly higher (all P<0.05). Multiple logistic regression analysis showed that educational years (OR=0.785, 95 % confidence interval[CI]0.662-0.930, P=0.005) and serum GSH (OR=1.291, 95 % CI 1.087-1.534, P=0.004) were the influencing factors of cognitive impairment in postmenopausal women, and ROC curve analysis showed that area under curve of the combination in diagnosing cognitive impairment was 0.764, with a sensitivity of 0.750 and a specificity of 0.676. Conclusion The serum levels of ferroptosis-related indexes system Xc^-, GPX4, GSH, ACSL4, ROS, LPO and MDA are increased in postmenopausal women. Serum GSH is associated with cognitive impairment, and its combination with educational years may be a potential marker for early diagnosis of cognitive impairment in postmenopausal women.