Obesity is considered an independent risk factor for increased hospital length of stay and can be an obstacle to a safe discharge. Although typically prescribed in the outpatient setting, initiating glucagon-like peptide-one receptor agonists (GLP-1RAs) in the inpatient setting can be efficacious in reducing weight and increasing functional status. We report the use of GLP-1RA therapy with liraglutide and subsequent transition to subcutaneous semaglutide weekly in a 37-year-old female with severe obesity, weighing 694 lbs (314 kg) with a body mass index (BMI) of 108 kg/m. Multiple medical and socioeconomic factors impaired the patient from being safely discharged and ultimately led to prolonged hospitalization. The patient received 31 consecutive weeks of GLP-1RA therapy in the inpatient setting along with a very low-calorie diet (800 kcal/day). Initiation and up-titration doses were completed using liraglutide for a total of five weeks. Subsequently, the patient was transitioned to receive weekly semaglutide and completed 26 weeks of therapy. At the end of week 31, the patient's weight decreased by 174 lbs (79 kg), or 25% of baseline weight, and BMI decreased from 108 to 81 kg/m. GLP-1RAs offer a promising avenue for weight loss interventions in patients with severe obesity in addition to lifestyle modifications. The weight loss observed in our patient at the halfway point of the total treatment duration is a milestone in the pathway to gaining functional independence and meeting the criteria for future bariatric surgery. Semaglutide, a GLP-1RA, can be an effective intervention for severely obese patients with BMI greater than 100 kg/m.