Throughout the course of evolution, bacteria have developed signal transduction tools such as two-component systems (TCSs) to meet their demands to thrive even under the most challenging environmental conditions. One TCS called MtrAB is commonly found in and is implicated in cell wall metabolism, osmoprotection, cell proliferation, antigen secretion, and biosynthesis of secondary metabolites. However, precisely how the MtrAB TCS regulates the bacterial responses to external environments remains unclear. Here, we report that the MtrAB TCS regulates the cell envelope response of alkali-tolerant bacterium sp. strain DQ12-45-1b to extreme alkaline stimuli. We found that under alkaline conditions, an mutant exhibited both reduced growth and abnormal morphology compared to the wild-type strain. Electrophoretic mobility shift assay analysis showed that MtrA binds the promoter of the gene critical for cell wall homeostasis, suggesting that MtrA directly controls transcription of this regulator. In conclusion, our findings demonstrate that MtrAB TCS is involved in controlling the bacterial response to alkaline stimuli by regulating the expression of the cell wall homeostasis regulator MraZ in sp. DQ12-45-1b, providing novel details critical for a mechanistic understanding of how cell wall homeostasis is controlled. Microorganisms can be found in most extreme environments, and they have to adapt to a wide range of environmental stresses. The two-component systems (TCSs) found in bacteria detect environmental stimuli and regulate physiological pathways for survival. The MtrAB TCS conserved in is critical for maintaining the metabolism of the cell wall components that protects bacteria from diverse environmental stresses. However, how the MtrAB TCS regulates cell wall homeostasis and adaptation under stress conditions is unclear. Here, we report that the MtrAB TCS in sp. DQ12-45-1b plays a critical role in alkaline resistance by modulating the cell wall homeostasis through the MtrAB-MraZ pathway. Thus, our work provides a novel regulatory pathway used by bacteria for adaptation and survival under extreme alkaline stresses.