Isolated sphenoid sinusitis (ISS) is a rare but potentially serious condition, often leading to severe complications due to delayed diagnosis and treatment. This case report discusses a 75-year-old male with type 2 diabetes mellitus who presented with severe left-sided headache and neck pain. Diagnostic imaging revealed isolated sphenoid sinusitis with prevertebral extension, a rare occurrence that highlights the potential for deep neck space involvement. The patient underwent endoscopic transnasal incision and drainage of the prevertebral abscess with a left sphenoidotomy, resulting in full recovery without recurrence. This case emphasizes the importance of prompt recognition and intervention in ISS, particularly in cases with atypical presentations. The report also discusses the complex anatomy of the sphenoid sinus and its surrounding structures, the broad differential diagnosis of sphenoid sinus opacification, and the necessity for a multidisciplinary approach to management. This case contributes to the limited literature on ISS with prevertebral extension and underscores the critical need for early diagnosis and aggressive treatment to prevent severe complications.