This study aims to observe the effects of modified Xiaojianzhong decoction (MXD) and its components, paeoniflorin(PF) and trans-cinnamaldehyde (TCA), on the behavior of chronic unpredictable mild stress (CUMS) rats, hippocampal mitochondrial damage and ferroptosis-related proteins. A total of 50 SPF SD rats were randomly assigned to a control group (Con, n=7) and a model group (n=43). Rats in the model group were modeled using the CUMS method for four weeks. Eight rats that failed to model were eliminated, and successfully modeled rats were randomly divided into a model group (Mod, n=7), a MXD group (n=7), a PF group (n=7), a TCA group (n=7), and a fluoxetine group (n=7). Rats in each group were administered the pre-defined intervention for four weeks, and the CUMS protocol was continued. After the drug intervention, the forced swimming test (FST) and open field test (OFT) were performed. Changes in serum superoxide dismutase (SOD) and malondialdehyde (MDA) levels were detected using enzyme-linked immunosorbnent assay. Meanwhile, hippocampal reactive oxygen species (ROS), mitochondrial respiratory chain complex Ⅰ (complex Ⅰ) and complex III levels were detected using test kits. The expression levels of the ferroptosis-related proteins cyclooxygenase-2 (COX-2), long chain fatty Acyl-CoA synthetase 4 (FACL-4), ferritin, and glutathione peroxidase 4 (GPX4) in the hippocampus were detected via Western blot analysis. The rats in the Mod group exhibited increased immobility time in the FST and reduced movement distance and duration in the OFT compared with the Con group, and the MXD and its active ingredients decreased the immobility time of CUMS rats in the FST while enhancing their movement distance and duration in the OFT. Serum SOD levels were lower in the Mod group compared to the Con group,whereas MDA levels were higher.Concurrently,serum SOD levels in the MXD,PF,and TCA groups were higher while MDA levels were lower compared to the Mod group.Moreover,ROS levels were higher in the hippocampus of the rats in the Mod group compared to the Con group.And ROS levels were lower in the MXD,PF,and TCA groups compared to the Mod group.Compared with the Con group,the hippocampal levels of complex I and complex III in the Mod group were lower.Contrastingly,compared with the Mod group,the levels of complex I and complex III in the MXD,PF,and TCA groups were higher.Compared with the Con group,the hippocampal expression levels of FACL-4 and COX-2 were higher in the Mod group,whereas those of ferritin heavy polypeptide 1 (FTH-1) and GPX4 were lower.Compared with the Mod group,the hippocampal levels of FACL-4 and COX-2 in the MXD group,PF group,and TCA group were lower,whereas those of FTH-1 and GPX4 were higher.MXD and its active ingredients ameliorated behavioral changes in CUMS rats,and its mechanism may be related to inhibiting neuronal ferroptosis in the hippocampus and oxidative stress response,as well as enhancing mitochondrial function.