Oral mucositis (OM) is an oral complication of chemotherapeutics agents such as 5-Fluorouracil (5-FU), which is a broadly consumed drug in the chemotherapy preparations of the colorectal and bosom malignant growths and the aerodigestive plot's tumors. Silymarin is acquired from Silybum marianum (milk thorn), it has been utilized therapeutically for quite a long time as a hepatoprotective and cytoprotective medication. Pharmacological information shows that silymarin has direct impacts on cell-managing instruments, reactive oxygen species (ROS) rummaging properties affirmed in new examinations, demonstrating a possibility to diminish harmful impacts of different medications, for example, cisplatin, amiodarone. The aim of this study was to assess the protective effect of Silymarin treatment to prevent chemotherapy induced oral mucositis by 5-FU is the objective of this study via the assessment of serum CP and S100A12 / EN-RAGE levels. A total of 50 albino Wistar rats of both genders were divided randomly into five groups. Three groups treated with Silymarin in different doses 2 mg/kg, 4 mg/kg, and 6 mg/kg, the fourth group treated with 1ml of Dimethyl Sulfoxide (DMSO) as placebo for 10 days, after that treated by two doses of 5-FU (60 mg/kg). The fifth group is the control which treated by 5-FU 60 mg/kg only. The results of this study showed the significant silymarin protection for the chemotherapy induced buccal mucositis in the 4 and 6 mg/kg compared to 2 mg/kg silymarin doses, showed no mucositis ulceration, and dose-dependent effect compared to severe clinical manifestations of oral mucositis lesion patterns such as erythema, extensive ulcerations, and abscesses that shown in control groups IV and V. The conclusion of this study proved the dose-dependent protective efficacy of Silymarin treatment for chemotherapy induced oral mucositis