In Mycobacterium tuberculosis (Mtb), persisters are genotypically drug-sensitive bacteria that nonetheless survive antibiotic treatment. Persisters represent a significant challenge to shortening TB treatment and preventing relapse, underscoring the need for new therapeutic strategies. In this study, we screened 2,336 FDA-approved compounds to identify agents that enhance the sterilizing activity of standard anti-TB drugs and prevent the regrowth of persisters. Netupitant (NTP), an FDA-approved antiemetic, emerged as a promising candidate with bacteriostatic activity on its own. However, in combination with isoniazid (INH) and rifampicin (RIF), NTP eliminated viable Mtb cells within 7 days, achieving a >6-log reduction in colony-forming units (CFUs) compared to the 2.5-log reduction observed with INH-RIF alone. NTP also demonstrated broad-spectrum efficacy, enhancing the activity of multiple TB drugs, including ethambutol, moxifloxacin, amikacin, and bedaquiline. Notably, NTP retained its potency under hypoxic and caseum-mimicking conditions, both of which are known to enrich for non-replicating, drug-tolerant cells. Interestingly, under hypoxic conditions, NTP demonstrated strong tuberculocidal activity, achieving an approximate 4-log CFU reduction, whereas high-dose INH-RIF was ineffective. Transcriptomic analysis revealed that NTP primarily disrupts cellular bioenergetics, with significant downregulation observed in activities associated with the electron transport chain, oxidative phosphorylation, NADH-ubiquinone oxidoreductase, succinate dehydrogenase, and ATP synthesis. While further studies are required to decipher the mechanism of action and resistance profile of NTP, and to assess its in vivo efficacy, these findings underscore its potential as a promising adjunct to existing TB therapies.