Skeletal muscles serve both in movement and as endocrine organs. Myokines secreted by skeletal muscles activate biological functions within muscles and throughout the body via autocrine, paracrine, and/or endocrine pathways. Skeletal muscle atrophy can influence myokine expression and secretion, while myokines can impact the structure and function of skeletal muscles. Regulating the expression and secretion of myokines through a pharmacological approach is a strategy for alleviating skeletal muscle atrophy. Natural products possess complex structures and chemical properties. Previous studies have demonstrated that various natural products exert beneficial effects on skeletal muscle atrophy. This article reviewed the regulatory effects of natural products on myokines and summarizeed the research progress on skeletal muscle atrophy associated with myokine regulation. The focus was on how small-molecule natural products affect the regulation of interleukin 6 (IL-6), irisin, myostatin, and IGF-1 expression. We contend that the development of small-molecule natural products targeting the regulation of muscle factors holds promise in combating skeletal muscle atrophy.