Septic myopathy, also known as ICU acquired weakness (ICU-AW), is a characteristic clinical symptom of patients with sepsis, mainly manifested as skeletal muscle weakness and muscular atrophy, which affects the respiratory and motor systems of patients, reduces the quality of life, and even threatens the survival of patients. Melatonin is one of the hormones secreted by the pineal gland. Previous studies have found that melatonin has anti-inflammatory, free radical scavenging, antioxidant stress, autophagic lysosome regulation, mitochondrial protection, and other multiple biological functions and plays a protective role in sepsis-related multiple organ dysfunction. Given the results of previous studies, we believe that melatonin may play an excellent regulatory role in the repair and regeneration of skeletal muscle atrophy in septic myopathy. Melatonin, as an over-the-counter drug, has the potential to be an early, complementary treatment for clinical trials. Based on previous research results, this article aims to critically discuss and review the effects of melatonin on sepsis and skeletal muscle depletion.