Williams-Beuren syndrome (WBS) is a rare multisystem disorder caused by a hemizygous deletion of the elastin gene on chromosome 7q11.23. WBS patients have characteristic skeletal features and dental anomalies accompanied by mental retardation, a friendly outgoing personality, and mild to moderate intellectual disability or learning problems. In this case report, we present the combined orthodontic and surgical treatment of a WBS patient with an isolated cleft palate through a long-term follow-up from the age of 5 to 24 years. During the period of active treatment, comprehensive orthodontic treatment combined with maxillary anterior segmental distraction osteogenesis and prosthetic treatment using dental implants were effective in dramatically improving the patient's malocclusion. The patient's mental abilities and the cooperation shown by the patient and her family were crucial for the success of this complex and long-term treatment course.