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Tuberculosis (TB) is a top-ten cause of death worldwide. Successful treatment is often limited by insufficient diagnostic capabilities, especially at the point of care in low-resource settings. The ideal diagnostic must be fast, cheap, and require minimal clinical resources while providing high sensitivity, selectivity, and the ability to differentiate live from dead bacteria. We describe here the development of a Fast, Luminescent, and Affordable Sensor of Hip1 (FLASH) for the diagnosis and monitoring of drug sensitivity ofMycobacterium tuberculosis(Mtb). FLASH is a selective chemiluminescent substrate for theMtbprotease Hip1 that when processed, produces visible light that can be measured with a high signal to noise ratio using inexpensive sensors. FLASH is sensitive to fmol of recombinant Hip1 enzymein vitroand can detect as few as thousands ofMtbcells in culture or in human sputum samples within minutes. The probe is highly selective forMtbcompared to other non-tuberculous mycobacteria and can distinguish live from dead cells. Importantly, FLASH can be used to measure antibiotic killing ofMtbin culture with greatly accelerated timelines compared to traditional protocols. Overall, FLASH has the potential to enhance both TB diagnostics and drug resistance monitoring in resource-limited settings.One Sentence SummaryA luminescent probe enables sensitive detection ofMycobacterium tuberculosisfor diagnostics, treatment monitoring, and drug susceptibility testing.