INTRODUCTION: Oral squamous cell carcinoma (OSCC) is the sixth common cancer. Surgery remains the main way of OSCC treatment. It is followed by radiotherapy and chemotherapy either alone or in combination. Conventional chemotherapy is associated with systemic toxicity. Doxorubicin (DOX) is one of the effective chemotherapeutic drugs. Direct delivery of chemotherapeutics may reduce their side effects. OBJECTIVES: The study aimed to evaluate the anticancer effect of intratumoral injection of DOX in the treatment of chemically induced OSCC. MATERIALS AND METHODS: Thirty-two Syrian golden male hamsters were used as an animal model for oral carcinogenesis. After cancer induction, the hamsters were divided into 4 groups; saline-intraperitoneal (IP), saline-intratumoral, DOX-IP, and DOX-intratumoral. The clinical evaluation of the proposed treatment included measuring the change in tumor volume before and after treatment, whereas, the histological evaluation included calculating the apoptotic index. The proliferative activity was evaluated immunohistochemically by minichromosome maintenance 3 (MCM3). In all statistical results, a p < 0.05 was considered significant. RESULTS: The DOX-IP and DOX-intratumoral groups reported significant decrease in the mean tumor volume. The apoptotic index (AI) was significant only in the DOX-intratumoral group. The MCM3 immunostain showed significant decrease in the values of mean area percent (MA%) and mean optical density (MOD) in DOX-intratumoral group, whereas the DOX-IP group was insignificant in its MA% and MOD. CONCLUSION : Local delivery of this chemotherapeutic drug may be suitable alternative to the systemic administration, with superior anticancer effect in the treatment of superficial tumors.