Spexin (SPX) is a 14 amino acid length peptide hormone which was discovered using bioinformatic tools. It is extensively expressed in central and peripheral tissues and secreted into circulation in response to metabolic stress. Recent studies revealed that SPX acts as a multifunctional peptide in various metabolic processes such as body weight, food intake, energy balance, glucose and lipid metabolism, lipid storage, salt–water balance, and arterial blood pressure. Endogenous SPX is sensitive to metabolic changes, and circulating levels of SPX have been shown to be reduced in chronic diseases such as obesity, diabetes, and insulin resistance. Moreover, in fish and rodent models, systemic SPX treatment has positive effects on metabolism including reduced food intake, fat mass, lipid accumulation, and inflammation, improved insulin sensitivity, energy expenditure, and organ functions which are underlying mechanisms in diseases. Taken together, these findings suggest that SPX is a potential drug target for the development of new pharmacological strategies to cure metabolic diseases. This review focuses on metabolo-protective properties of SPX and discusses novel insights into the biology and mechanism of SPX in the pathogenesis of diabetes, obesity, non-alcoholic fatty liver disease, metabolic syndrome, polycystic ovary syndrome, cardiovascular diseases, and kidney diseases, which are considerable global health problems.