Background: Exposure to mild, uncontrollable, and persistent stress strongly correlates with several mental and physical problems. This study aimed to assess the ameliorative effect of metformin (MET) on the parotid salivary gland of rats exposed to chronic unpredictable mild stress (CUMS). Materials and methods: A total of 40 male albino rats were used in the study and divided into four groups (n = 10 each): control group, CUMS group: exposed to CUMS for four weeks, fluoxetine (FLX) group: exposed to CUMS for four weeks and treated orally with 10 mg/kg/day FLX for two weeks, and MET group: exposed to CUMS for four weeks and treated orally with 50 mg/kg MET daily for 2 weeks. The specimens from parotid salivary glands were obtained and processed for histological and ultrastructural examinations, and expressions of proliferating cell nuclear antigen (PCNA) and neurotrophin-3 (NT-3) gene using real-time polymerase chain reaction. Results: Exposure to CUMS significantly reduced body weight. Histologically, CUMS-induced hydropic degeneration in acinar cells, and the ultrastructural findings showed the acinar cells with many intracellular vacuoles, irregular, shrunken nuclei with condensed chromatin, deteriorated mitochondria, and expanded rough endoplasmic reticulum. Besides reducing immunoexpression of PCNA with the highest level of NT-3 gene expression, treatment with MET improves body weight, restores the histological architecture of salivary glands, and protects against neurodegenerative disorders as it reduces the NT-3 expression. Conclusion: Treatment with MET, as an antidepressant drug, is a more effective approach than treatment with FLX in the short term.