<p>Diabetes mellitus (DM) is a significant contributor to tuberculosis (TB) incidence and poor treatment outcomes. This study explored the impact of isoniazid preventive therapy (IPT) on <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>)-specific T-cell memory phenotypes and function among participants with latent TB infection and DM (LTBI-DM) at baseline and after 6 months of IPT; and compared the responses to healthy controls (HC). Peripheral blood mononuclear cells were stimulated with ESAT-6 and CFP-10 peptide pools to analyse CD4⁺ and CD8⁺ T-cell responses using flow cytometry. In LTBI-DM participants, effector memory CD4⁺ and CD8⁺ T cells were decreased post-IPT, suggesting a shift towards a less-activated state or differentiation into other subsets. CXCR5 expression on both CD4⁺ and CD8⁺ T cells was upregulated, while PD-1 expression was downregulated post-IPT, indicating reduced T-cell exhaustion and improved homing capabilities. Lastly, IL-17&#xa0;A and IL-13 production in CD4⁺ and CD8⁺ T cells was increased post-IPT, respectively, which play a role in enhanced <i>Mtb</i> infection control. The post-IPT T-cell alterations were similar to normal HC levels. These findings suggest that IPT modulates and normalises specific T-cell memory phenotypes and functional responses in LTBI-DM participants, potentially contributing to improved long-term immunity and protection against TB. This study highlights the importance of preventive therapy in high-risk populations, and larger studies with more extended follow-up are needed to assess long-lasting IPT effects.</p>