Objective To explore the effects of Astragalus polysaccharide (APS) on nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and serum oxidation indicators in chronic unpredictable mild stress (CUMS)-induced depression model mice. Methods Thirty-six BALB/c mice were randomly assigned to normal control group, CUMS group, CUMS＋fluoxetine group (CUMS＋F group), or CUMS＋APS group, with 9 mice in each group. The mice in the CUMS, CUMS＋F and CUMS＋APS groups were stimulated by CUMS for 4 weeks to construct depression models. After successful modeling, the mice in the CUMS＋F group were intraperitoneally injected with 10 mg/kg of fluoxetine daily, the mice in the CUMS＋ APS group were given 400 mg/kg of APS by gavage daily, and the mice in the normal control group and CUMS group were given an equal volume of normal saline for 4 weeks. The depression status of the mice was observed by behavioral experiment after drug intervention. After 4 weeks of drug intervention, the eye socket blood was collected, and the levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), superoxide anion (O₂^·) and hydroxyl radical (·OH) in the mouse serum were detected using enzyme-linked immunosorbent assay. The expression of Nrf2 in mouse hippocampal tissue was detected by Western blotting. Results Compared with the CUMS group, the immobility time of mice was significantly shortened in the CUMS＋F group and CUMS＋APS group in the tail suspension experiment (both P＜0.01), while the sucrose preference rate, crossing times of open-field test, and the entry times of open arm and time spent in open arm in the elevated cross maze experiment were significantly increased (P＜0.05, P＜0.01); the level of MDA in the mouse serum was significantly decreased (both P＜0.05), while the levels of SOD, GSH-Px,O₂^· and ·OH were significantly increased (P＜0.05, P＜0.01); and the expression level of Nrf2 in the mouse hippocampal tissue was significantly increased (P＜0.05, P＜0.01). Conclusion APS can improve the depressive state of CUMS-induced depression model mice, which may be achieved by regulating Nrf2 pathway in hippocampal tissue and serum oxidative indicators.