Tuberculosis (TB) maintains its infamous status regarding its detrimental effect on global health, causing the highest mortality by a single infectious agent. The presence of resistance and immune compromising disease favours the disease in maintaining its footing in the health care burden despite various anti-TB drugs used to fight it. Main factors contributing to resistance and difficulty in treating disease include prolonged treatment duration (at least 6 months) and severe toxicity, which further leads to patient non-compliance, and thus a ripple effect leading to therapeutic non-efficacy. The efficacy of new regimens demonstrates that targeting host factors concomitantly with the Mycobacterium tuberculosis (M.tb) strain is urgently required. Due to the huge expenses and time required of up to 20 years for new drug research and development, drug repurposing may be the most economical, circumspective, and conveniently faster journey to embark on. Host-directed therapy (HDT) will dampen the burden of the disease by acting as an immunomodulator, allowing it to defend the body against antibiotic-resistant pathogens whilst minimizing the possibility of developing new resistance to susceptible drugs. Repurposed drugs in TB act as host-directed therapies, acclimatizing the host immune cell to the presence of TB, improving its antimicrobial activity and time taken to get rid of the disease, whilst minimizing inflammation and tissue damage. In this review, we, therefore, explore possible immunomodulatory targets, HDT immunomodulatory agents, and their ability to improve clinical outcomes whilst minimizing the risk of drug resistance, through various pathway targeting and treatment duration reduction.