Macrophage activation is an essential component in host defense against mycobacterial infection. Invasive mycobacteria induce not only inflammatory responses but also metabolic changes of macrophages. Recent studies showed that inflammatory macrophages induced by a slow growing and virulent M. tuberculosis strain have increased glycolytic metabolism and reduced mitochondrial respiration, but not enough known for the rapid growing mycobacteria. In our study, we infected human macrophages with M. massiliense (M. mass), a strain of M. abscessus complex, and examined metabolic and functional changes of macrophages to investigate immunometabolic responses to rapid growing and virulent mycobacteria. M. mass-infected macrophages showed an increase in lactate secretion, representing increased intracellular glycolytic activity. Extracellular flux analyses also demonstrated a shift toward glycolytic metabolism in M. mass-infected macrophages. Furthermore, M. mass infection induced activation of PI3K-Akt-mTOR signaling pathway, mainly promoting aerobic glycolysis and cell survival. Interestingly, treatment of infected macrophage with 2-deoxy-d-glucose, a glycolysis inhibitor, induced enhancement of bactericidal responses of macrophage and impair intracellular growth of M. mass. These results imply regulation of glycolytic pathway can drive a phenotypic switch of inflammatory macrophages to enhance host defense against mycobacteria. Thus, rewiring the metabolic pathway of host cells can serve as therapeutic approaches to improve treatment outcome of drug-sensitive and drug-resistant mycobacterial diseases.