Abstract: Objective: This study aimed to investigate the ameliorative effects and underlying mechanisms of Pediococcus acidilactici I1-2, a strain isolated from traditional fermented foods of the Qinghai-Tibet Plateau, on depressive behavior induced by chronic stress through in vivo experiments. Methods: C57BL/6J mice were randomly assigned to three groups: control, model, and P. acidilactici I1-2 intervention groups. A depression model was established by subjecting the mice to six weeks of chronic unpredictable mild stress (CUMS). Depressive and anxiety-like behaviors were assessed using the open field test, elevated plus maze, tail suspension test, and sucrose preference test. Cortical levels of serotonin (5-HT) and dopamine (DA) were quantified via high-performance liquid chromatography (HPLC). Additionally, levels of malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) in the hippocampus and serum were measured, alongside mRNA expression levels of inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-22) in the hippocampus. Microglial activation in the brain was evaluated using IBA-1 immunofluorescence staining. Results: Intervention with P. acidilactici I1-2 significantly increased the time spent and distance traveled in the central area of the open field (P<0.01) and enhanced exploration time in the open arms of the elevated plus maze (P<0.05). Furthermore, immobility time in the tail suspension test was significantly reduced (P<0.01), and the sucrose preference index was markedly elevated (P<0.01). The intervention also significantly increased cortical 5-HT and DA levels (P<0.05), reduced MDA levels in the hippocampus and serum (P<0.01), and elevated GSH levels and SOD activity (P<0.01). In terms of neuroinflammation, P. acidilactici I1-2 significantly downregulated the gene expression of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 (P<0.05), upregulated the expression of the anti-inflammatory cytokine IL-22 (P<0.05), and attenuated microglial activation in the brain (P<0.05). Conclusion: Pediococcus acidilactici I1-2, as a foodborne probiotic, significantly ameliorates depressive behavior induced by chronic stress. These findings provide a foundation for the development and application of probiotics in functional foods targeting brain health.