PURPOSE: The diversity and composition of the oral and gut microbiota of depressed rats were analyzed to explore the microbiological etiology of major depressive disorder (MDD). METHODS: The depressed rat model was established by inducing chronic unpredictable mild stress (CUMS). After the establishment of the model, body weight measurements and behavioral tests were conducted. The diversity and composition of oral and gut microbiota were analyzed using 16SrRNA sequencing. RESULTS: There were significant differences in the alpha and beta diversity of the oral microbiota of rats in the CUMS and control groups. The top three most abundant genera in the oral microbiota were , , and . Linear discriminant analysis effect size (LEfSe) analysis showed that the abundance of decreased and that of Psychrotrophs increased in the CUMS group, and the differences were statistically significant. The top three most abundant genera in the gut microbiota were and . LEfSe analysis showed that the abundance of decreased in the CUMS group, and the difference was statistically significant. Spearman correlation analysis was performed to analyze the differential microbiota and depression-like behavior, which showed that differential microbiota significantly correlated with body weight, total distance traveled, average speed, and number of rearing. Spearman correlation analysis of oral and gut differential microbiota demonstrated a strong positive correlation between in the oral cavity and in the intestine (=0.64-0.73, <0.01); along with a strong negative correlation between in the oral cavity and , in the intestine(=-0.51--0.72, <0.05). CONCLUSION: Significant differences were observed in the diversity and composition of oral and gut microbiota between the CUMS depression model and control groups. Modulating the oral and gut microbiota may have positive effects on MDD.