Inhibition of β-lactamase by clavulanate (Clav) sensitizes multi- and extensively drug-resistant Mycobacterium tuberculosis (Mtb) strains towards β-lactams such as amoxicillin (Amox). However, the underlying mechanism of how Mtb responds to Amox-Clav combination (Augmentin; AG) is not characterized. We integrated global expression profiling with the protein-protein interaction landscape and generated a genome-scale network of Mtb in response to AG. In addition to specific targets (e.g., peptidoglycan biosynthesis and β-lactamase), the response to AG was also centered on redox-balance, central carbon metabolism (CCM), and respiration in Mtb . We discovered that AG modulates superoxide levels, NADH/NAD+ balance and mycothiol redox potential (EMSH) of Mtb. Higher intra-mycobacterial EMSH potentiates mycobactericidal efficacy of AG, whereas lower EMSH induces tolerance. Further, Mtb responds to AG via a redox-sensitive transcription factor, WhiB4. MtbΔwhiB4 displayed higher expression of genes involved in β-lactam resistance along with those mediating respiration, CCM and redox balance. Moreimportantly, WhiB4 binds to the promoter regions and represses transcription of genes involved in β-lactamase expression in a redox-dependent manner. Lastly, while MtbΔwhiB4 maintained internal EMSH, exhibited greater β-lactamase activity and displayed AG-tolerance, overexpression of WhiB4 induced oxidative shift in EMSH and repressed β-lactamase activity to aggravate AG-mediated killing of drug-sensitive and -resistant strains of Mtb. Altogether, work demonstrate that efficacy of β-lactam\β-lactamase inhibitor combination can be attenuated by elevating mycobacterial antioxidant capabilities and potentiated by impairing redox buffering capacity of Mtb. The functional linkage between β-lactams, redox balance, and WhiB4 can be exploited to potentiate AG action against drug-resistant Mtb.