Background <p>Human immunodeficiency virus (HIV) and tuberculosis (TB) coinfection pose a substantial global health burden, with each infection amplifying the immune and metabolic impacts of the other. Investigating the compounded metabolic disruptions in HIV/TB coinfection and how these are modulated by antiretroviral therapy (ART) offers information into disease mechanisms and therapeutic strategies.</p> Methods <p>This study used untargeted proton nuclear magnetic resonance metabolomics to characterize the urine samples from three participant groups: healthy controls, treatment-naive HIV/TB coinfected individuals, and ART-treated HIV/TB coinfected individuals.</p> Results <p>Significant metabolite shifts were observed across gut microbiota, energy, amino acid, and carbohydrate metabolism. Metabolomic profiles of HIV/TB coinfection suggested mitochondrial perturbation, markers of insulin resistance, and microbial dysbiosis. ART was associated with partial restoration of mitochondrial function, stabilization of gut microbiota, and reduced oxidative stress. However, glucose dysregulation appeared to persist. Key metabolites, including phenylacetylglycine and trans-aconitic acid, emerged as potential differential markers for coinfection and treatment response.</p> Conclusion <p>ART modulates metabolic pathways disrupted by HIV/TB coinfection, showing partial improvements but leaving glucose metabolism dysregulated. These findings highlight the potential of targeted metabolic monitoring to optimize coinfection treatment strategies. Further investigations are needed in larger cohorts to validate these results and better understand coinfection pathophysiology.</p>