Gardner syndrome (GS) is a rare autosomal dominant disorder that can present with craniomaxillofacial abnormalities. The identification of osteomas or craniomaxillofacial abnormalities can therefore serve as a marker of this condition, facilitating early referral and diagnosis. A 17-year-old female with GS was referred for the management of severe limited mouth opening, causing a major problem for routine endoscopy to monitor the gastrointestinal alterations of GS. Clinical and radiological evaluations showed multiple osteomas in the mandibular angle, condylar and coronoid regions bilaterally and maximum mouth opening of 8 mm. The patient underwent surgery for osteoma removal and bilateral customized alloplastic total temporomandibular joint replacement (TMJ-TJR). At the 2-year follow-up, the patient showed improvements in quality of life, with a maximum mouth opening of 34 mm, allowing routine upper endoscopy to be performed. This is the first report of GS, a rare and challenging craniomaxillofacial abnormality, treated with TMJ-TJR. A comprehensive overview of the patient’s clinical presentation, diagnostic assessment, treatment planning, and outcomes is provided.