This study identifies a 393-gene transcriptional signature in whole blood that distinguishes active tuberculosis (TB) from latent and healthy controls, correlating with radiological disease extent and reverting after treatment. A subset of latent TB patients exhibit signatures similar to active TB. An 86-gene signature discriminating active TB from other inflammatory and infectious diseases is also identified. Modular and pathway analysis reveals that the TB signature is dominated by a neutrophil-driven interferon (IFN)-inducible gene profile, including both IFN-γ and Type I IFNαβ signaling. Flow cytometry and purified cell analysis suggest that this signature reflects changes in cellular composition and altered gene expression. The study highlights the role of Type I IFNαβ signaling in TB pathogenesis and provides potential diagnostic and prognostic biomarkers for TB.This study identifies a 393-gene transcriptional signature in whole blood that distinguishes active tuberculosis (TB) from latent and healthy controls, correlating with radiological disease extent and reverting after treatment. A subset of latent TB patients exhibit signatures similar to active TB. An 86-gene signature discriminating active TB from other inflammatory and infectious diseases is also identified. Modular and pathway analysis reveals that the TB signature is dominated by a neutrophil-driven interferon (IFN)-inducible gene profile, including both IFN-γ and Type I IFNαβ signaling. Flow cytometry and purified cell analysis suggest that this signature reflects changes in cellular composition and altered gene expression. The study highlights the role of Type I IFNαβ signaling in TB pathogenesis and provides potential diagnostic and prognostic biomarkers for TB.