<p>Chronic intracellular bacterial infections persist within host cells by evading immune clearance, imposing prolonged metabolic stress on the host. In response, the immune system undergoes metabolic reprogramming to sustain prolonged defense. A key feature of this reprogramming is the shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, which enhances pro-inflammatory and antimicrobial responses. Concurrently, fatty acid and amino acid catabolism provide additional metabolic support. Beyond shaping immune function, these metabolic shifts also influence the trajectory of infection by altering the host-pathogen metabolic interplay. In this review, we focus primarily on <i>Mycobacterium tuberculosis</i> (Mtb) infection and integrate quantitative flux analyses of carbon and nitrogen distribution, emphasizing how these metabolic changes connect to epigenetic regulation. We also explore metabolic reprogramming in five representative immune cell types—comprising both innate and adaptive immune cells—to elucidate how their distinct metabolic profiles influence host defense mechanisms and disease progression. Building on these foundations, we propose an innovative metabolic competition model between host and pathogen, offering new insights into the intricate interplay of metabolic networks in chronic intracellular infections.</p> Graphical abstract <p>Upon chronic infection with intracellular bacteria, immune cells undergo metabolic reprogramming, leading to alterations in metabolic flux and significant changes in the levels of specific metabolites. These key metabolites regulate cellular functions and signaling pathways by modulating epigenetic modifications and the activity of critical enzymes, thereby exerting dual effects—either enhancing host antimicrobial defense or supporting pathogen survival and persistent infection</p> <p></p>