Background: Salivary gland diseases are induced by radiotherapy, autoimmune diseases, inflammation, trauma, and obstructive lesions. They result in functional gland impairment which harms oral health and quality of life. Exosomes are extracellular nanoparticles produced by a variety of cells including stem cells. Exosomes facilitate the paracrine functions of the releasing cells, and they are easily absorbed and can integrate with target cells resulting in long-lasting effects. Objective: To identify the therapeutic role of exosomes in the histological and biochemical changes in the submandibular gland (SMG) of adult male albino rats after duct ligation. Materials and methods: Forty adult male albino rats were included in this study. They were distributed in three main groups: control, duct-ligated and treated groups. Exosomes were isolated from the saliva of healthy rats. The treated group received salivary exosomes one week after duct ligation. At the end of the study, the SMG was removed from all groups and two samples were obtained from each gland: one for antioxidant measurement and RNA extraction with subsequent gene expression determination. The other was used for histopathological and immunohistochemical analysis. Results: The ligated group revealed degenerative histological changes including vacuolated cytoplasm, apoptotic nuclei, congested blood vessels and cellular infiltrate. Increased area percentage of both collagen fibers and S100 immunoreactivity was detected. The treated group showed an amelioration in the histological and immunohistochemical picture. After treatment with exosomes, a significant increase in all antioxidants was recorded. This was accompanied by an increase in both c-kit and cytokeratin-5 gene expression. Conclusion: There were improved histological, immunohistochemical and biochemical alterations after treatment with salivary exosomes. So, salivary exosomes could be a possible modality in treating SMG diseases.