Background <p>HIV/TB coinfection poses significant challenges due to complex interactions between both pathogens and the metabolic disruptions they induce. Although antiretroviral treatment (ART) has transformed disease management, its impact on metabolism is not fully understood. Metabolomics offers an in-depth approach to explore the metabolic changes in this coinfected population, providing information into disease mechanisms and the effects of ART.</p> Methods <p>This exploratory study used untargeted urine gas chromatography mass spectrometry metabolomics to profile metabolic alterations in treatment-naïve HIV/TB coinfected patients and those on ART. Healthy controls were included for comparison. Metabolite changes were analysed using univariate statistical methods, including Kruskal-Wallis tests and pairwise comparisons, to identify key metabolites associated with coinfection and ART.</p> Results <p>Findings revealed significant disruptions in several metabolic pathways. Mitochondrial dysfunction was evident, contributing to altered lipid metabolism, impaired energy production, and increased cardiovascular risk. Disruptions in glucose metabolism, including compromised insulin secretion, were observed, alongside evidence of gut dysbiosis linked to inflammation and microbial imbalance. These metabolic disturbances were also associated with increased oxidative stress, reflected in changes to protein metabolism and the development of cachexia. Although ART partially alleviated some metabolic alterations, disruptions remained evident in treated patients.</p> Conclusion <p>This study provides a comprehensive view of the metabolic disturbances in HIV/TB coinfection and the impact of ART. Our findings suggest that persistent mitochondrial dysfunction, altered lipid metabolism, and gut dysbiosis contribute to ongoing metabolic imbalances, underscoring the need for targeted therapeutic strategies to address these challenges.</p> Graphical Abstract <p></p>