Fluorouracil (5-FU) is one of the most popular chemotherapeutic agents used in various cancer therapy protocols. Cell-free therapy utilizing exosomes is gaining increased popularity as a safer option due to concerns over potential tumor progression following stem cell therapy. Parotid glands of albino were treated with a single bone marrow mesenchymal stem cell (BMMSC)-derived exosomes injection (100 μg/kg/dose suspended in 0.2 mL phosphate-buffered saline [PBS]), a single 5-Fu injection (20 mg/kg), and BMMSC-derived exosomes plus 5-FU and compared to control group (daily saline injections). After 30 days, the parotid glands were examined using qualitative histological evaluation, immunohistochemical evaluation using rabbit polyclonal mouse antibody to Ki-67, caspase 3, and , as well as quantitative real-time polymerase chain reaction (RT-PCR) to evaluate gene expression of , , and . Histological examination of the parotid gland revealed that BMMSC-derived exosomes restored the glands' architecture and repaired most of the distortion created by 5-FU. Immunohistochemical expression of tumor proliferation and cell death markers were restored to normal levels in the exosome-treated groups that were similar to the control group. Furthermore, BMMSC-derived exosomes reversed the effects of 5-FU on quantitative gene expression levels and showed a significant decrease in ( < 0.001) and a significant increase in ( < 0.0001) and ( < 0.05) when compared to 5-FU treatment. Within the limitations of the current study, BMMSC-derived exosomes have the potential to counteract the cytotoxic effects of 5-FU on the parotid glands of rats in vivo. Further studies are deemed necessary to simulate clinical scenarios.