Background and objectives: Methotrexate (MTX) had been used for many years and complications usually encountered during treatment especially in cancer patients. The aim of the present study was to determine the preventive and early-stage anti cytotoxic effects of green tea on the histology of the submandibular gland of rats treated by high single dose of methotrexate. Materials and methods: The study included 36 Albino rats. Twelve animals were used in the pilot study to find the maximum toxic dose, and the other twenty four were divided into four groups, vehicle treated control group, green tea extract treated control group (40 mg/kg/day), methotrexate treated group (80 mg/kg), and methotrexate and green tea extract treated group. Submandibular glands excisions were then performed. Histopathological examination was performed with hematoxylin-eosin, Masson’s trichrome, and PAS stains. Cell proliferation was examined using the Ki-67 antibody and anti apoptotic effect was determined based on Bcl-2 staining. Results: In the methotrexate and green tea extract treated group a non significant difference in the Ki-67 expression (p>0.01) and a significant increase in Bcl-2 expression (p<0.01) were seen in comparison with the methotrexate treated group. Conclusion: Green tea aqueous extract at a concentration of 40 mg/kg/day produced a protection against methotrexate induced cytotoxicity in rat submandibular gland by increasing the expression of Bcl-2.