Squamous cell carcinoma (SCC) is a squamous epithelial neoplasm. They are solitary tumors with indolent expansion, are locally invasive, and can be seen in any part of the body. The most commonly affected sites are the head, orbital region, and genitalia of horses. Solar irradiation is one of the main causes, especially in depigmented and hairless areas. SCC is the neoplasm most frequently described in equine species. Several treatments have been described in horses, usually associated with surgical excision with different adjuvant therapies, hoping for a better prognosis and a decrease in cancer-related morbidity. Since the recurrence rates are high, especially in regions that do not have an adequate safety margin after tumor removal, multimodality treatment is essential. The aim of this report was to describe a case of perianal SCC in a Quarter Horse colt clinically treated with the immunomodulatory drug imiquimod. A three-year-old, grey-haired, male Quarter Horse was examined for diagnosis and treatment of an ulcerative lesion in the perianal region. According to the owner's report, the lesion appeared approximately 16 months ago. Based on the medical history and clinical examination, SCC was suspected. To confirm the clinical diagnosis, a biopsy was performed. Histological examination showed infiltrative neoplastic proliferation from the epidermis, consisting of malignant keratinocytes associated with hyperkeratosis, neutrophilic infiltrate, and foci of ulceration. The underlying dermis exhibited an intense chronic inflammatory infiltrate. The findings were compatible with SCC. Due to the location and extension of the lesion, we decided to use immunomodulatory therapy with imiquimod. After 16 weeks of imiquimod application, the lesion completely regressed. The horse was clinically followed for two years, and no recurrence was identified.