The molecular mechanisms of pathogen persistence within host cells are emerging hotspots, and one of the causes of its persistence is the acid resistance of bacteria. Currently, tuberculosis remains a serious threat to global public health and it is caused by Mycobacterium tuberculosis. In particular, acid resistance of M. tuberculosis and its persistence within macrophages contribute significantly to tuberculosis. Investigations have uncovered three major mechanisms underlying its acid resistance: the control of proton entry, metabolic regulation of intracellular acid-base balance and regulation of the two-component signaling system. In this review, we summarize the overall regulation network of M. tuberculosis in the acidic environment, aiming at providing a new overall idea for treating M. tuberculosis persistence and exploring new targets for tuberculosis control.