Florid cemento-osseous dysplasia (FCOD) is a benign fibro-osseous lesion that predominantly affects middle-aged women and may occasionally be associated with simple bone cysts (SBC), posing a diagnostic challenge. A 49-year-old female presented with a three-month history of dull pain in the lower right posterior region, radiating to the head, neck, and right shoulder. Clinical examination revealed mild cortical expansion, left submandibular lymphadenitis, and tenderness over the maxillary sinuses and cervical muscles. Radiographic evaluation demonstrated multiple radiolucent areas in the mandible associated with hypercementosis and sclerotic changes. Biochemical investigations, including serum calcium, phosphorus, alkaline phosphatase, and parathyroid hormone levels, were within normal limits. Histopathological examination confirmed the diagnosis of florid cemento-osseous dysplasia associated with a simple bone cyst. The coexistence of these lesions can result in atypical clinical and radiographic features, making accurate diagnosis challenging. This case highlights the importance of integrating clinical findings with radiographic, biochemical, and histopathological investigations for the diagnosis of complex fibro-osseous lesions of the jaws. A comprehensive and multidisciplinary diagnostic approach is essential for distinguishing FCOD associated with SBC from other mixed or radiolucent jaw lesions and for guiding appropriate patient management.