The gut microbiome has emerged as a growing focus of research and public health interest, leading to the frequent exploration of probiotic dietary supplements as potential treatments for various disorders, such as anxiety and depression. In the present report, changes in inflammation and microbiome composition were assessed in model mice exhibiting depressive-like behaviors that were exposed to the probiotic Lactobacillus zhachilii HBUAS52074T. It was found that L. zhachilii HBUAS52074T alleviated the severity of depressive-like behaviors while increasing serum 5-HT concentrations. Moreover, L. zhachilii HBUAS52074T modulated the composition of the gut microbiota, resulting in a decrease in the abundance of Prevotella and an increase in the abundance of Lactobacillus. Additionally, supplementation with L. zhachilii HBUAS52074T enhanced intestinal barrier function and reduced inflammation in peripheral blood, as well as in the hippocampal and prefrontal cortical tissues. Correlational analyses indicated that the abundance of Lactobacillus was positively correlated with the social interaction ratio, time spent in the center, entries into the center, as well as serum 5-HT and serum IL-10 levels but negatively correlated with immobility time. Overall, chronic social defeat stress was found to be associated with inflammation and the exacerbation of depressive-like behaviors. The above findings suggested that L. zhachilii HBUAS52074T supplementation was sufficient to alter the parameters. Collectively, these data suggest that L. zhachilii HBUAS52074T, derived from naturally fermented foods, may possess therapeutic potential for the treatment of depression.