Tuberculosis (TB), caused by the pathogen Mycobacterium tuberculosis (Mtb), remains a significant global health challenge. Despite the availability of vaccines and antibiotics, Mtb's ability to persist within host cells complicates its eradication and highlights the urgent need for innovative therapeutic approaches. Host-directed therapies (HDTs), which aim to bolster the host's immune defenses against Mtb, represent a promising strategy.Here, I explore the use of HDTs by screening epigenetic modifiers to reprogram macrophages, the primary cellular niche of Mtb, for enhanced bacterial control. A high-throughput screen of an epigenetic compound library identified several promising candidates across diverse pathways, including PRC2 inhibitors. Notably, PRC2-targeting compounds demonstrated remarkable efficacy in enhancing macrophage function by preserving mitochondrial integrity and increasing reactive oxygen species (ROS) production, leading to a significant reduction in Mtb burden both in vitro and in vivo. Importantly, genetic knockout of EZH2, the core enzymatic component of PRC2 in macrophage recapitulated the protective effects observed with pharmacological inhibitors, demonstrating that both genetic and drug-based targeting of PRC2 independently validated its role in macrophage-mediated Mtb control. Additionally, I repurposed Tilorone, commonly known as an interferon inducer, as an HDT for TB. Tilorone was found to reprogram macrophage metabolism, boosting glycolysis and TCA cycle activity, which in turn elevated ROS and nitric oxide (NO) levels essential for controlling intracellular Mtb. Short-term in vivo treatment with Tilorone, when combined with antibiotics, showed a marked reduction in bacterial burden. However, prolonged treatment led to metabolic exhaustion, underscoring the need for precise dosing strategies to maximize therapeutic benefits. Together, these findings emphasize the therapeutic potential of HDTs, using both epigenetic modifiers and Tilorone, to optimize macrophage function and enhance antibiotic efficacy against TB. This approach advances our understanding of TB pathogenesis and opens new avenues for treatment by targeting the host’s immune system rather than the pathogen directly, addressing persistent challenges in TB control. These contributions mark an important step toward developing HDT-based strategies that could significantly improve long-term outcomes for TB patients.