Tuberculosis (TB) is one of the oldest leading health diseases of mankind, caused by the bacteria Mycobacterium tuberculosis. It is still the major cause of high mortality and morbidity worldwide from a single infectious agent. Plant species belonging to the genus Halosarcia (formerly known as Salicornia) are known for their various medicinal properties like antioxidant, hepatoprotective, immunomodulatory, antimicrobial, etc., but not evaluated for their antimycobacterial property. The present study aimed to investigate the potential of Halosarcia indica (Willd.) (formerly known as Salicornia brachiata Roxb.), a halophytic plant, a source of antitubercular agents. The study involved the preparation of various extracts from different parts of the plant and the evaluation of their inhibitory activities against Mycobacterium tuberculosis H37Rv using in vitro and in vivo assays. It was observed that the aqueous extract of the roots had the highest anti-TB activity with minimum inhibitory concentration (MIC) of 50 µg/mL and a ten-fold reduction of M. tuberculosis bacilli in the lungs of treated mice. Further fractionation of aqueous extract of roots using butanol, MeOH:CHCl3, MeOH, MeOH:H2O, and H2O yielded fractions with varying anti-TB activity. The subfraction SF3K obtained from fraction 2 (F-2) showed the highest potency, with MIC ≤ 3.125 µg/mL and an increase of 5 days in the mean survival time of M. tuberculosis-infected and treated (with SF3K) mice. This subfraction was found to be non-cytotoxic (in vitro) and non-toxic (during in vivo efficacy evaluation). The present study, for the first time, provides scientific evidence for the use of H. indica in the treatment of tuberculosis.