Skeletal muscle disorders are dramatically increasing with human aging with enormous sanitary costs and impact on the quality of life. Preventive and therapeutic tools to limit onset and progression of muscle frailty include nutrition and physical training. Melatonin, the indole produced at nighttime in pineal and extra-pineal sites in mammalians, has recognized anti-aging, anti-inflammatory, and anti-oxidant properties. Mitochondria are the favorite target of melatonin, which maintains them efficiently, scavenging free radicals and reducing oxidative damage. Here, we discuss the most recent evidence of dietary melatonin efficacy in age-related skeletal muscle disorders in cellular, preclinical, and clinical studies. Furthermore, we analyze the emerging impact of melatonin on physical activity. Finally, we consider the newest evidence of the gut-muscle axis and the influence of exercise and probably melatonin on the microbiota. In our opinion, this review reinforces the relevance of melatonin as a safe nutraceutical that limits skeletal muscle frailty and prolongs physical performance.