Tuberculosis (TB) continues to be a global public health emergency responsible for approximately 1.3 million deaths annually. Enduring the existing TB challenges, the emergence of “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2), a similar respiratory infection threatened the success of TB control over the past few years. Contemplating the irreversible damage of the human immunodeficiency virus (HIV), one of the leading immune-suppressive conditions, a similar or worst expected with this synergism: TB-HIV-SARS-CoV-2. Therefore, an integrated approach is much demanded before the impending revolution, "Next Global Pandemic". The advancement of molecular diagnostic techniques, blood transcriptomics uncovered the importance of studying the cross-talk between host and pathogens. RNA-sequencing is a high-throughput sequencing technique allowing detailed characterization of gene expression profiles. With the impact of SARS-CoV-2 on host immunity, pathogen-derived biomarker identification is more disease-specific and constrains individual variations faced during host biomarker identification. However, several technical hurdles are encountered during the study of intracellular pathogens like Mycobacterium tuberculosis. The development of advanced RNA-sequencing techniques to tackle the issues targeting the host and pathogen interactions is in their infancy and restricted to in-vitro studies. Few studies on serum exosomal RNA-sequencing of active and latent TB patients enlightened the path of TB biomarker discovery urging the necessity of more studies. Thus, this review will explicitly discuss the existing TB diagnostic tools to understand where we stand in TB diagnosis and the recent advancements in blood transcriptomics emphasizing the importance of targeting the pathogen-derived biomarkers as a potential source for future diagnostics.