Background: Oral mucositis (OM) is a common inflammatory complication among cancerous patients as an ad verse effect of chemotherapy and radiotherapy. The aim of this study was to evaluate the effects and identify the appropriate route of administration of extract of Zizyphus jujuba in 5-flurouracile induced OM induction in golden hamster. Materials and Methods: In a prospective randomized double blind animal study, OM was induced in 56 male golden hamsters by 5-FU (60 mg/kg) on days 0, 5, and 10 of the study. The cheek pouch was scratched with a sterile needle on once daily on days 3 and 4. On days 14-17, 300 mg/kg dietary and 20% Z. jujuba gel and gel base groups were treated and then compared with a control group. Microscopic scores and pouch content of malondialdehyde (MDA), plus activities of superoxide dismutase and myeloperoxidase in pouch tissue were evaluated. Results: Histopathology scores of mucositis were lower in the systemic and 20% Z. jujuba gel groups than the gel base and control groups ( P <0.05). Also, lower MDA level and higher activities of MPO and SOD were detected in the systemic and 20% Z. jujuba gel groups in comparison to the gel base and control groups ( P <0.001). Conclusions: The use of Z. jujuba hydroalcoholic extract in systemic and topical forms may be associated with reduced intensity of OM, diminished concentration of MDA, and increased activity of MPO and SOD on induced OM in golden hamster undergoing 5-FU consumption