Smith-Magenis syndrome (SMS) is a rare genetic disorder characterized by intellectual disability, behavioral challenges, sleep disturbances, and obesity. Managing obesity in SMS is complex due to the behavioral dysregulation. This case involves a patient with SMS who experienced significant weight gain from early in childhood, developing complications such as type 2 diabetes, dyslipidemia, and steatotic liver disease. Initial management with lifestyle changes was insufficient, leading to progressive weight gain. At age 18 years, subcutaneous semaglutide was introduced, resulting in marked improvements in impulsivity, food cravings, and weight control. However, because of a global shortage of this medication, at age 21 years, she was switched to the oral formulation of semaglutide, which led to a relapse in violent behavior, increased food intake, and weight regain. When subcutaneous semaglutide became available again, it was reinstated, stabilizing her weight and behavior. This case underscores the potential of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in managing both obesity and behavioral symptoms in SMS. While injectable GLP-1 RAs show promise, further research is needed to determine why they may be more effective than oral formulations. Further studies are needed to confirm the effectiveness of GLP-1 RAs and the dosage and explore alternative treatments for long-term obesity management in genetic syndromes.