The co-infection of HIV and tuberculosis (TB) poses a significant global health challenge, requiring combination therapy involving antiretroviral therapy (ART) for HIV and anti-TB medications. This review aims to provide a comprehensive analysis of drug–drug interactions (DDIs) between anti-HIV and anti-TB drugs, as well as potential adverse effects resulting from their concomitant use. The altered host immune response in individuals with HIV significantly increases their susceptibility to TB infection, as CD4+ T cell depletion weakens the immune system's ability to control TB. ART has significantly enhanced life expectancy for HIV patients, but it is not curative. Mycobacterium tuberculosis (Mtb) is the causative agent of TB, and its treatment involves a combination of first-line agents such as Rifampin, Isoniazid, Pyrazinamide, and Ethambutol. The development of drug resistance in Mtb strains necessitates the use of second-line agents. DDIs between ARTs and anti-TB medications can impact treatment outcomes, efficacy, safety, and patient well-being. The article discusses current therapeutic approaches for HIV and TB, including the use of NRTIs, NNRTIs, INSTIs, PIs, CCR5 inhibitors, and Ibalizumab for HIV, and the first-line and second-line agents for TB. It also highlights the importance of personalized and comprehensive care for individuals co-infected with HIV and TB, considering cytotoxicity, DDIs, and patient compliance. Potential therapeutic strategies, such as dual-targeted heterodimers, targeting metabolites, and transcript silencing, are explored to improve treatment outcomes and address the challenges posed by HIV-TB co-infection.The co-infection of HIV and tuberculosis (TB) poses a significant global health challenge, requiring combination therapy involving antiretroviral therapy (ART) for HIV and anti-TB medications. This review aims to provide a comprehensive analysis of drug–drug interactions (DDIs) between anti-HIV and anti-TB drugs, as well as potential adverse effects resulting from their concomitant use. The altered host immune response in individuals with HIV significantly increases their susceptibility to TB infection, as CD4+ T cell depletion weakens the immune system's ability to control TB. ART has significantly enhanced life expectancy for HIV patients, but it is not curative. Mycobacterium tuberculosis (Mtb) is the causative agent of TB, and its treatment involves a combination of first-line agents such as Rifampin, Isoniazid, Pyrazinamide, and Ethambutol. The development of drug resistance in Mtb strains necessitates the use of second-line agents. DDIs between ARTs and anti-TB medications can impact treatment outcomes, efficacy, safety, and patient well-being. The article discusses current therapeutic approaches for HIV and TB, including the use of NRTIs, NNRTIs, INSTIs, PIs, CCR5 inhibitors, and Ibalizumab for HIV, and the first-line and second-line agents for TB. It also highlights the importance of personalized and comprehensive care for individuals co-infected with HIV and TB, considering cytotoxicity, DDIs, and patient compliance. Potential therapeutic strategies, such as dual-targeted heterodimers, targeting metabolites, and transcript silencing, are explored to improve treatment outcomes and address the challenges posed by HIV-TB co-infection.