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A major challenge to the control and eventual eradication of Mycobacterium tuberculosis infection is this pathogen's prolonged dormancy. The heme‐based oxygen sensor protein DevS (DosS) plays a key role in this phenomenon, because it is a major activator of the transcription factor DevR. When DevS is active, its histidine protein kinase region is ON and it phosphorylates and activates DevR, which can induce the transcription of the dormancy regulon genes. Here, we have investigated the mechanism by which the ligation of molecular oxygen to a heme‐binding domain in DevS switches OFF its histidine protein kinase region. To shed light on the oligomerization states of this protein and possible protein‐surfaces of interaction, we used analytical gel filtration, together with dynamic light scattering, fluorescence spectroscopy and chemical crosslinking. We found that DevS exists as three major species: an octamer, a tetramer and a dimer. These three states were observed for the concentration range between 0.5 and 20 μm DevS, but not below 0.1 μm. Levels of DevS in M. tuberculosis are expected to range from 5 to 26 μm. When this histidine protein kinase was OFF, the DevS was mainly tetrameric and dimeric; by contrast, when the kinase was ON, the protein was predominantly octameric. The changes in quaternary structure were rapid upon binding to the physiological signal. This finding represents a novel strategy for switching the activity of a two‐component heme‐based sensor. An enhanced understanding of this process might potentially lead to the design of novel regulatory agents that target the multimer interfaces for treatment of latent tuberculosis. The oxygen sensor DevS (DosS) of Mycobacterium tuberculosis is found as a mixture of oligomers. There is a rapid change in the quaternary structure of this protein upon binding to the physiological signal. In the inactive state, DevS bound to oxygen is mainly in the dimer and tetramer states. However, in the active state, in anaerobic conditions, DevS is found mainly as an octamer, which may be responsible for the activity of the protein. [ABSTRACT FROM AUTHOR]