The role of CD39 pathway in Th1 cell function in tuberculosis (TB) is rarely elucidated. The present study aims to investigate the modulating mechanism of CD39 pathway during Mycobacterium tuberculosis (MTB) infection. CD39 expression was examined on host immune cells among patients with TB. The relationship between CD39 expression and Th1 cell function was analysed. Patients with TB displayed dramatically higher CD39 expression on Th1 cells than healthy controls, and a significantly increased expression of surface markers, including activation, exhaustion and apoptosis markers, were noted in CD39(+) Th1 cells in comparison with CD39(-) Th1 cells. Conversely, CD39 expression on Th1 cells was associated with diminished number of polyfunctional cells producing Th1-type cytokines, and CD39(+) Th1 cells showed obviously lower proliferation potential. Notably, tetramer analysis demonstrated a predominant CD39 expression on TB-specific CD4(+) cells, which was associated with higher apoptosis and lower cytokine-producing ability. Transcriptome sequencing identified 27 genes that were differentially expressed between CD39(+) and CD39(-) Th1 cells, such as IL32, DUSP4 and RGS1. Inhibition of CD39 pathway could enhance the activation, proliferation and cytokine-producing ability of Th1 cells. Furthermore, there was a significantly negative correlation between CD39 expression on Th1 cells and nutritional status indicators such as lymphocyte count and albumin levels, and we observed a significant decline in CD39 expression on Th1 cells after anti-TB treatment. CD39 is predominantly expressed on TB-specific Th1 cells and correlated with their exhausted function, which suggests that CD39 could serve as a prominent target for TB therapy.