Semaglutide, a medication used for type 2 diabetes and weight loss, may have unexpected side effects such as sarcopenia and age-related loss of muscle mass and strength. A 74-year-old male patient with type 2 diabetes and dyslipidemia presented with progressive fatigue over 2 years. He experienced a significant decline in walking endurance and speed despite the absence of joint pain or other obvious causes. He had a history of ocular myasthenia gravis and localized prostate cancer, both of which were well-managed. Further investigation revealed a weight loss of 8 kg after starting semaglutide treatment for diabetes. Physical examinations revealed reduced muscle bulk and strength. Extensive investigations, including blood tests, imaging, and cardiopulmonary exercise testing, have ruled out other potential causes of fatigue. The patient's fatigue improved after reducing the semaglutide dose and implementing a tailored exercise program that focused on muscle strengthening. This case highlights the potential contribution of semaglutide to muscle mass loss and subsequent fatigue, particularly among older adults.