Surgical management of oral cancer in a patient with severe comorbidities can pose many difficult challenges to the surgical team. A 48-year-old male patient who was suffering from long-standing, advanced ankylosing spondylitis (AS) presented with oral cancer. On evaluation, the tumor in the left buccal mucosa was found to be keratinizing squamous cell carcinoma of stage IVA [American Joint Committee on Cancer (AJCC)–tumor, node, metastasis (TNM) staging] and was planned for surgical resection. Due to AS, the patient's trunk and neck movements were severely restricted, along with trismus and restricted jaw movements. Surgical intervention under general anesthesia in such patients is associated with a substantial risk of spinal injury. The trismus and fixity of the neck rendered an exceedingly difficult surgical position for both the anesthesiologist and the head and neck surgeon. The anesthesiologist was successful in establishing a secured airway by performing awake bronchoscope-guided nasotracheal intubation. The neck of the patient had to be supported by pillows instead of a routine neck extension position used for neck dissections. Wide excision of the entire tumor with bite resection and left-sided modified neck dissection was conducted without any positional change of the neck. Reconstruction was conducted with the left anterolateral thigh flap. There were no surgery-related complications, and the healing of the surgical wounds was satisfactory. The patient was discharged from ward care after 8 days. The pathological staging was pT3N3b, and starting from the 5th week of postsurgery, the patient received adjuvant chemoradiation over 6 weeks. Despite many difficulties that were encountered during management, the patient was able to withstand and recover well. Ankylosing spondylitis (AS), as a comorbidity in head and neck cancer cases, can pose significant challenges to the surgical team. Although previous surgical experience and skills matter, good preoperative preparation and adapting the techniques to the needs of the patient will help in achieving surgical goals, prevent any complications, and ensure a good outcome for the patient.