Mycobacterium tuberculosis (M.tb) infection caused communicable disease tuberculosis (TB) is a major cause of ill health and one of the leading causes of death worldwide. Protein encoded by region of deletion (RD) of M.tb mediated the pathogenic properties of M.tb through inducing inflammation response or disrupting host cell metabolism. We cloned and purified Rv2653 protein from RD13 to explore its regulatory effect on host macrophages. We found Rv2653 protein promoted the glycolysis level and upregulated the expression of glycolytic key enzymes HK2 and LDHA of THP1 cells. Furthermore, Rv2653 induced glycolysis contributes to the activation of NLRP3 inflammasome. Rv2653 activated the mTORC1 signaling pathway, and the mTORC1 inhibitor NR1 blocked Rv2653-induced HK2, LDHA and NLRP3 expression. siRNA interfering HK2 or LDHA significantly inhibited the activation of NLRP3 inflammasome by Rv2653, blocked Rv2653 triggered inflammatory factors IL-1β, IL-6, TNF-α, ROS and NO, and promoted the survival of BCG in THP1 cells. Altogether, Rv2653 promotes the glycolysis process by activating mTORC1 signaling pathway, activates NLRP3 inflammasome and the release of inflammatory factors, ultimately inhibits the intracellular survival of BCG in THP1 cells. Therefore, we revealed Rv2653-induced anti-M.tb immune mechanisms which contributes to the development of new anti-TB strategy.