Tuberculosis is emerging as a major global health issue for the under-developed regions across the world including India’s North East. Importantly, the incidence of multidrug-resistant (MDR) strain of Mycobacterium tuberculosis (MTB), the causative agent of TB is increasing. Furthermore, the disease is associated with stigma, and therefore people’s wholehearted participation in care, and research support is lacking. Here, we report the development of novel research methodologies through a process of participatory action research (PAR) in India’s Northeast region (NER). The region is economically and socially underdeveloped having approximately 10% higher incidences of TB cases reported than the rest of the country. We have taken an indigenous knowledge system (IKS) based PAR approach, where a century-old local philosophy, Vedic altruism (Jiva Upakara Cikitsha Tantra) has been integrated into our research. Our goal has been to integrate philosophy, clinical care, and the latest clinical, microbiology, and cell biology research tools into one cohesive “knowledge emergence” hub, and then connect it with world’s outstanding research hubs to develop a global PAR against TB. Through this unique PAR-based approach, we were able to identify the stem cell niche as an important factor in TB dormancy, reactivation and MDR evolution. Importantly, we also discovered a natural aerosol-based TB vaccination mechanism. In this paper, we describe various methodologies that we have established as a part of the IKS/PAR-based TB research process. These methodologies include the PAR-based clinical care and monitoring, isolation of live MTB from the peripheral blood and bone marrow-derived progenitor cells, culture and drug-sensitivity test, the challenge of MTB DNA extraction and whole genome sequencing (WGS) from a small population of MTB intracellular to stem cells. We have also developed methodologies to detect viable but non culturable (VBNC) MTB of smear-negative pulmonary TB patients, as well as patients suffering from non-tuberculosis mycobacterium (NTM) infections. These methodologies now enable us to detect patients with an early stage of MDR evolution and compensatory mutation by isolating MTB intracellular to circulating progenitor cells. Importantly, the PAR setup now enables us to collaborate with the world’s leading scientific communities to further our knowledge of TB pathogenesis.