We present a case report of a 26-year-old female suffering from Coffin–Siris Syndrome, who underwent orthodontic treatment and surgery to solve her malocclusion and to improve her aesthetics and functional occlusion. Methods: The presurgical phase involved multibracket self-ligating attachments, namely a Damon prescription. The patient underwent maxillofacial surgery to correct the severe skeletal malocclusion and to relocate the bone bases to the right position. Post-surgical orthodontic treatment was performed to complete the alignment. Results: The patient’s aesthetics and functional abilities improved. Conclusions: Syndromic patients can undergo orthodontic treatment if comorbidities and collaboration allow it. The support and collaboration of families and psychotherapists must be considered, but clinical cases of syndromic patients can be faced and solved. Obviously, each syndromic patient is considered unique, and the risk–benefit ratio must be correctly assessed for each one.