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Background: The treatment of depression with acupuncture has been documented. The mechanism behind acupuncture's curative and preventative effects is still unknown. Methods: The current study examined the effects of acupuncture on depression -like behaviors in a rat model of chronic unpredictable mild stress (CUMS), while also exploring its potential mechanisms. A total of six groups of rats were randomly assigned: control, CUMS, acupuncture, fluoxetine, acupoint catgut embedding and sham acupoint catgut embedding. Fluoxetine (2.1 mg/kg) and acupoint catgut embedding were used for comparative research to acupuncture. The modelling evaluation is measured by body weight and behavior tests. Western blotting and reverse transcription-polymerase chain reaction were used to detect the proteins and mRNA expression of Silent information regulator 1 (Sirt1)/ nuclear factor-erythroid 2 -related factor 2 (Nrf2)/ heme oxygenase-1 (HO -1)/ Glutathione peroxidase 4 (GPX4) pathway in the hippocampus. The expression of oxidative stress (OS) -related proteins and inflammatory cytokines in the serum was detected with ELISA. Immunofluorescence showed microglia and astrocytes activity in the hippocampus. Results: Acupuncture and fluoxetine could alleviate CUMS-induced depression -like behaviors. Acupuncture was also found to effectively reverse the levels of MDA, SOD, GSH, GSH-PX and T-AOC, IL -18, IL -6 and TNF-alpha in the serum of CUMS-induced rats. Rats with CUMS showed decreased levels of Sirt1, Nrf2, HO -1 and GPX4 in the hippocampus, while acupuncture treatment could partly reverse the diminished effects. In addition, acupuncture treatment significantly reduced the activation of hippocampal microglia and astrocytes in CUMS-induced rats. Conclusion: The study's findings indicate that acupuncture has the potential to mitigate depression -like behaviors in rats induced with CUMS by mitigating OS and reducing neuroinflammation.