Canine oral papilloma is a benign tumor of young dogs and caused by papillomavirus. The possible role of papillomavirus infection in the development of oral squamous cell carcinoma has recently been studied, but it has not been elucidated in veterinary medicine yet. A one-year-old, mixed, spayed, female dog was presented with severely disseminated oral lesions, lethargy, and weight loss. Physical examination of the patient revealed severely disseminated oral papillomatous lesions in the entire oral cavity and the complete blood test showed mild non-regenerative anemia and pancytopenia. In addition, the patient was found seropositive by the SNAP 4Dx Plus test for Ehrlichia canis. Histopathologic examination of oral lesions was performed using Hematoxylin and Eosin (HE) staining and immunohistochemistry for p16, antibody which increases in infections caused by papillomavirus. Histopathology revealed the histologic features of oral papilloma in association with squamous cell carcinoma. Cytoplasmic and nuclear positive reactions for p16 protein were observed within the neoplastic cells in the immunohistochemical examination. Thereafter, the dog was treated with combined therapy of vincristine, antibiotic, radiotherapy, and high doses of vitamin C. After long-term treatment, the dog completely recovered from the lesions. In this report, it was aimed to present a possible role of papilloma in the development of oral squamous cell carcinoma with the clinical, histopathological, immunohistochemical findings and treatment procedure.