Metabolic reprogramming plays important roles in development and progression of nasopharyngeal carcinoma (NPC), but the underlying mechanism has not been completely defined. In this work, we foundINSL5 was elevated inNPCtumor tissue and the plasma ofNPCpatients. PlasmaINSL5 could serve as a novel diagnostic marker forNPC, especially for serumVCA-IgA-negative patients. Moreover, higher plasmaINSL5 level was associated with poor disease outcome. Functionally,INSL5 overexpression increased, whereas knockdown of its receptorGPCR142 or inhibition ofINSL5 reduced cell proliferation, colony formation, and cell invasionin vitroand tumorigenicityin vivo. Mechanistically,INSL5 enhanced phosphorylation and nuclear translocation ofSTAT5 and promoted glycolytic gene expression, leading to induced glycolysis in cancer cells. Pharmaceutical inhibition of glycolysis by 2-DGor blockade ofINSL5 by a neutralizing antibody reversedINSL5-induced proliferation and invasion, indicating thatINSL5 can be a potential therapeutic target inNPC. In conclusion,INSL5 enhancesNPCprogression by regulating cancer cell metabolic reprogramming and is a potential diagnostic and prognostic marker as well as a therapeutic target forNPC.