Condyloma acuminata is a cutaneous manifestation of human papillomavirus (HPV), with lesions varying in clinical presentation, ranging from small, sessile, or pedunculated growths to flat papules or large cauliflower-like plaques. Condyloma acuminata are categorized into high-risk and low-risk genotypes based on their association with carcinomas. High-risk HPV genotypes, HPV 16, 18, 31, 33, and 35, are more commonly associated with malignant transformation into squamous cell carcinoma (SCC). In contrast, low-risk subtypes, including HPV 6 and 11, are typically not associated with SCC. The development of SCC in this context is exceptionally rare, with malignant transformation likely being secondary to chronic infection and persistent inflammation. A thorough clinical evaluation of all HPV-associated cutaneous lesions is sometimes necessary in order to assess malignant potential, including physical examination, biopsy, and gene testing. Treatment methods including topical agents and surgical debridement are utilized on a case-by-case basis, guided by clinical features and histopathology. Similarly, SCC arising from pre-existing HPV lesions is systematically evaluated, with consideration of tumor stage, depth, and patient comorbidities guiding treatment decisions. Here, we present a unique SCC case arising out of a large and long-standing condylomatous plaque on the thigh, expressing low-risk HPV subtype in a 71-year-old male. The diagnosis and management are discussed.