DevR/DosR is a key mediator of ‘dormancy’ adaptation in Mycobacterium tuberculosis in response to gaseous stresses such as hypoxia that inhibit aerobic mode of respiration. In the present study, a temporal analysis over a 1 year period has revealed robust expression of representative DevR regulon genes devR, hspX and tgs1, during long-term ‘dormancy’ adaptation to hypoxia. Notably, a predominant proportion of long-term hypoxia-adapted bacteria were characterized by their inability to grow on solid media, accumulation of triacylglycerols and recovery of growth in liquid media. Persistent expression of HspX and the accumulation of triacylglycerols reveal a previously underappreciated role of DevR during adaptation to extended hypoxia, and endorse DevR as an effective target for thwarting the sustained survival of ‘dormant’ subpopulation of M. tuberculosis.