Mycobacterium tuberculosis (Mtb) is a persistent intracellular pathogen intrinsically tolerant to most antibiotics. The specific factors which mediate this tolerance however remain incompletely defined. Here, we apply metabolomic profiling to discover a common set of metabolic changes associated with the activities of three clinically used TB drugs, isoniazid, rifampicin, and streptomycin. Despite targeting diverse cellular processes, all 3 drugs trigger activation of Mtb’s isocitrate lyases (ICLs), metabolic enzymes commonly assumed to be involved in replenishing of tricarboxylic acid (TCA) cycle intermediates. We further show that ICL-deficient Mtb strains are significantly more susceptible than wild type Mtb to all three antibiotics and that this susceptibility can be chemically rescued when Mtb is co-incubated with an anti-oxidant. These results identify a previously undescribed role for Mtb’s ICLs in antioxidant defense as a mechanism of antibiotic tolerance.