Mycobacterium tuberculosis (M. tb) is one of the successful pathogens and claim millions of deaths across the globe. The emergence of drug resistance in M. tb has created new hurdles in the tuberculosis elimination programme worldwide. Hence, there is an unmet medical need for alternative therapy, which could be achieved by targeting the host's critical signalling pathways that are compromised during M. tb infection. In this review, we have summarized some of the findings involving the modulation of host GPCRs in the regulation of the mycobacterial infection. Understanding the role of these GPCRs not only unravels signalling pathways during infection but also provides clues for targeting critical signalling intermediates for the development of GPCR‐based host‐directive therapy.LINKED ARTICLESThis article is part of GPCR Review Series. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/toc/10.1111/(ISSN)1476‐5381.GPCRReviews