Metabolic syndrome is a worldwide epidemic with the incidence in China reaching 24. 2%. It is a cluster of metabolic indicators that serve as risk factors for the development of diabetes and cardiovascular diseases. Fibroblast growth factor 21(FGF21) is a metabolic signaling regulator. Exogenous FGF21 analogues display various pharmacological effects, such as lowering blood glucose, lipids and body weight. However, the mechanism by which FGF21 regulates metabolism remains unclear. It may involve adiponectin-dependent pathways, non-adiponectin-dependent pathways, and central regulatory pathways of the brain. Clinical studies have found that high levels of FGF21 are closely associated with the occurrence, development, and poor prognosis of metabolic syndrome, indicating the presence of "FGF21 resistance". The review summarizes the latest research progress on the metabolic regulation mechanism of FGF21, aiming to provide new insights for clinical diagnosis, treatment, and further investigation of metabolic diseases.