Tuberculosis is a common and often deadly infectious disease caused by mycobacteria, mainly Mycobacterium tuberculosis and infrequently by other subspecies of the M. tuberculosis complex, such as M. bovis. Sodium hypochlorite (bleach) is routinely used in hospitals and health care facilities for surface sterilization; however, the modes of action of bleach on M. bovis BCG and how this organism develops resistance to sodium hypochlorite have not been elucidated. In this study, we performed a global toxicogenomic analysis of the M. bovis response to 2.5 mM sodium hypochlorite after 10 and 20 min. M. bovis BCG growth was monitored by measuring the quantity of ATP in picomoles produced over a short exposure time (10–60 min) to sodium hypochlorite. This study revealed significant regulation of oxidative stress response genes of M. bovis BCG, such as oxidoreductase, peroxidase, heat shock proteins and lipid transport, and metabolism genes. We interpreted this response as a potentially more lethal interplay between fatty acid metabolism, sulfur metabolism, and oxidative stress. Our results also suggest that sodium hypochlorite repressed transcription of genes involved in cell wall synthesis of M. bovis. This study shows that the treatment of M. bovis BCG with bleach inhibits the biosynthesis of outer cell wall mycolic acids and also induces oxidative damage.