Introduction: Extreme obesity (BMI ≥50 kg/m2) is a complex pathology to treat. One of the complications of extreme obesity is massive localized lymphedema (MLL), due to compromised lymphatic drainage. There is a lack of literature guiding the medical management of these conditions. Case Presentation: We present a 43-year-old male who was admitted to our specialized obesity center for weight management. His initial weight was 255 kg and BMI was 93.7 kg/m2. He suffered from massive multifocal lymphedema of his left leg. He was bedridden due to his condition and malnourished, as shown by multiple vitamin deficiencies. The patient received care from our multidisciplinary team including nurses, dieticians, physical therapists, and psychologists. Treatment with semaglutide was started in hospital and continued at home. The maximal dose used was 1 mg/week but decreased during follow-up to 0.25 mg/week to avoid malnutrition. Protein and nutritional supplements were added. At 28 weeks of therapy, the patient had lost 40 kg or 15.7% of his total body weight. His lymphedema decreased; he had lost at least 16 cm of his left thigh circumference. He was able to walk again and regain autonomy of his daily activities of living. Conclusion: Semaglutide can be effective in patients with extreme obesity, with the support of a multidisciplinary team in a specialized obesity center. It can also help decrease MLL. More data are needed to guide medical treatment of patients with extreme obesity and MLL.