Systemic sclerosis (SSc) is an autoimmune disease that can cause fibrosis in vital organs, often resulting in damage to the skin, blood vessels, gastrointestinal system, lungs, heart, and/or kidneys. Patients with SSc are also likely to develop microstomia, which can render dental treatment difficult and painful, thereby necessitating advanced anesthetic management. This is a case report of a 61-year-old woman with a history of SSc with microstomia, interstitial pneumonia, and gastroesophageal reflux disease in whom intravenous moderate sedation was performed using a combination of dexmedetomidine and ketamine for dental extractions. Both anesthetic agents are known to have analgesic effects while minimizing respiratory depression. Consequently, the increased discomfort caused by opening the patient’s mouth and stretching the buccal mucosa was sufficiently managed, permitting an increase in maximum interincisal opening and completion of treatment without complications. Patients with SSc present with serious comorbidities that can negatively impact anesthetic management, so the implementation of an anesthetic plan that takes such risks into account is required. Furthermore, emergency airway management is likely to be difficult in patients with microstomia. For intravenous moderate sedation, combined use of dexmedetomidine and ketamine, which have analgesic effects while minimizing respiratory depression, may be particularly effective in patients with SSc and microstomia.