The current study aims to show the diagnostic challenge of mandibular exposed necrotic bone in a patient with locally aggressive cutaneous squamous cell carcinoma of the lower lip and carrying risk factors for osteoradionecrosis and medication-related osteonecrosis of the jaws. In March 2023, an 80-year-old ex-farmer male patient complaining of feeding difficulty showed a 3 cm area of exposed bone in the left region of the mandible. In July 2020, the patient underwent an incisional biopsy of a lower labial cutaneous keratinizing squamous cell carcinoma, which developed within actinic cheilitis. The cancer was unresectable due to the extent of the local invasion; thus, the patient underwent radiotherapy. In February 2022, the cancer reached the left mandibular canal by completely infiltrating the homolateral canal of the mental nerve. Therefore, the oncologist prescribed cemiplimab and denosumab as palliative immunotherapy. The differential diagnosis included osteoradionecrosis, stage-III medication-related osteonecrosis of the jaws, and intraoral localization of the cutaneous squamous cell carcinoma. The oral surgeon performed a sequestrectomy under local anesthesia and antibiotic prophylaxis; a histological examination confirmed the hypothesis of medication-related osteonecrosis. The patient currently undergoes follow-up visits monthly; the combination of photobiomodulation therapy and cycles of antibiotics keeps the necrotic lesion steady, and the oncological therapy prevents the growth of the cutaneous squamous cell cancer. The current case supports the need for histological examination to resolve the diagnostic challenge of mandibular exposed necrotic bone and to differentiate among osteoradionecrosis, stage-III medication-related osteonecrosis of the jaws, and intraoral localization of cutaneous squamous cell carcinoma.